2,4-pyrimidinediamine compounds and their uses

ABSTRACT

The present invention provides 2,4-pyrimidinediamine compounds that inhibit the IgE and/or IgG receptor signaling cascades that lead to the release of chemical mediators, intermediates and methods of synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and prevention of diseases characterized by, caused by or associated with the release of chemical mediators via degranulation and other processes effected by activation of the IgE and/or IgG receptor signaling cascades.

1. CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/366,931, filed on Dec. 1, 2016, which is a continuation of U.S.patent application Ser. No. 14/812,829, filed Jul. 29, 2015, which is acontinuation of U.S. patent application Ser. No. 14/309,530, filed Jun.19, 2014, now issued as U.S. Pat. No. 9,133,133, which is a continuationof U.S. patent application Ser. No. 13/759,835, filed Feb. 5, 2013, nowissued as U.S. Pat. No. 8,853,397, which is a continuation of U.S.patent application Ser. No. 13/288,813, filed Nov. 3, 2011, now issuedas U.S. Pat. No. 8,410,266, which is a continuation of U.S. patentapplication Ser. No. 12/762,178, filed Apr. 16, 2010, now issued as U.S.Pat. No. 8,148,525, which is a continuation of U.S. patent applicationSer. No. 11/539,049, filed Oct. 5, 2006, now issued as U.S. Pat. No.7,820,819, which is a continuation of U.S. patent application Ser. No.10/355,543, filed Jan. 31, 2003, now issued as U.S. Pat. No. 7,557,210,which in turn claims benefit under 35 U.S.C. § 119(e) to U.S.Provisional Patent Application No. 60/353,333, filed Feb. 1, 2002; U.S.Provisional Patent Application No. 60/353,267, filed Feb. 1, 2002; U.S.Provisional Patent Application No. 60/399,673, filed Jul. 29, 2002; andU.S. Provisional Patent Application No. 60/434,277, filed Dec. 17, 2002,all of which prior applications are incorporated herein by reference.

2. FIELD OF THE INVENTION

The present invention relates generally to 2,4-pyrimidinediaminecompounds, pharmaceutical compositions comprising the compounds,intermediates and synthetic methods of making the compounds and methodsof using the compounds and compositions in a variety of contexts.

3. BACKGROUND OF THE INVENTION

Crosslinking of Fc receptors, such as the high affinity receptor for IgE(FcεRI) and/or the high affinity receptor for IgG (FcγRI) activates asignaling cascade in mast, basophil and other immune cells that resultsin the release of chemical mediators responsible for numerous adverseevents. For example, such crosslinking leads to the release of preformedmediators of Type I (immediate) anaphylactic hypersensitivity reactions,such as histamine, from storage sites in granules via degranulation. Italso leads to the synthesis and release of other mediators, includingleukotrienes, prostaglandins and platelet-activating factors (PAFs),that play important roles in inflammatory reactions. Additionalmediators that are synthesized and released upon crosslinking Fcreceptors include cytokines and nitric oxide.

The signaling cascade(s) activated by crosslinking Fc receptors such asFcεRI and/or FcγRI comprises an array of cellular proteins. Among themost important intracellular signal propagators are the tyrosinekinases. And, an important tyrosine kinase involved in the signaltransduction pathways associated with crosslinking the FcεRI and/orFcγRI receptors, as well as other signal transduction cascades, is Sykkinase (see Valent et al., 2002, Intl. J. Hematol. 75(4):257-362 forreview).

As the mediators released as a result of FcεRI and FcγRI receptorcross-linking are responsible for, or play important roles in, themanifestation of numerous adverse events, the availability of compoundscapable of inhibiting the signaling cascade(s) responsible for theirrelease would be highly desirable. Moreover, owing to the critical rolethat Syk kinase plays these and other receptor signaling cascade(s), theavailability of compounds capable of inhibiting Syk kinase would also behighly desirable.

4. SUMMARY OF THE INVENTION

In one aspect, the present invention provides novel2,4-pyrimidinediamine compounds that, as will be discussed in moredetail below, have myriad biological activities. The compounds generallycomprise a 2,4-pyrimidinediamine “core” having the following structureand numbering convention:

The compounds of the invention are substituted at the C2 nitrogen (N2)to form a secondary amine and are optionally further substituted at oneor more of the following positions: the C4 nitrogen (N4), the C5position and/or the C6 position. When substituted at N4, the substituentforms a secondary amine. The substituent at N2, as well as the optionalsubstituents at the other positions, may range broadly in character andphysico-chemical properties. For example, the substituent(s) may be abranched, straight-chained or cyclic alkyl, a branched, straight-chainedor cyclic heteroalkyl, a mono- or polycyclic aryl a mono- or polycyclicheteroaryl or combinations of these groups. These substituent groups maybe further substituted, as will be described in more detail below.

The N2 and/or N4 substituents may be attached directly to theirrespective nitrogen atoms, or they may be spaced away from theirrespective nitrogen atoms via linkers, which may be the same ordifferent. The nature of the linkers can vary widely, and can includevirtually any combination of atoms or groups useful for spacing onemolecular moiety from another. For example, the linker may be an acyclichydrocarbon bridge (e.g, a saturated or unsaturated alkyleno such asmethano, ethano, etheno, propano, prop[1]eno, butano, but[1]eno,but[2]eno, buta[1,3]dieno, and the like), a monocyclic or polycyclichydrocarbon bridge (e.g., [1,2]benzeno, [2,3]naphthaleno, and the like),a simple acyclic heteroatomic or heteroalkyldiyl bridge (e.g., —O—, —S—,—S—O—, —NH—, —PH—, —C(O)—, —C(O)NH—, —S(O)—, —S(O)₂—, —S(O)NH—,—S(O)₂NH—, —O—CH₂—, —CH₂—O—CH₂—, —O—CH═CH—CH₂—, and the like), amonocyclic or polycyclic heteroaryl bridge (e.g., [3,4]furano, pyridino,thiopheno, piperidino, piperazino, pyrazidino, pyrrolidino, and thelike) or combinations of such bridges.

The substituents at the N2, N4, C5 and/or C6 positions, as well as theoptional linkers, may be further substituted with one or more of thesame or different substituent groups. The nature of these substituentgroups may vary broadly. Non-limiting examples of suitable substituentgroups include branched, straight-chain or cyclic alkyls, mono- orpolycyclic aryls, branched, straight-chain or cyclic heteroalkyls, mono-or polycyclic heteroaryls, halos, branched, straight-chain or cyclichaloalkyls, hydroxyls, oxos, thioxos, branched, straight-chain or cyclicalkoxys, branched, straight-chain or cyclic haloalkoxys,trifluoromethoxys, mono- or polycyclic aryloxys, mono- or polycyclicheteroaryloxys, ethers, alcohols, sulfides, thioethers, sulfanyls(thiols), imines, azos, azides, amines (primary, secondary andtertiary), nitriles (any isomer), cyanates (any isomer), thiocyanates(any isomer), nitrosos, nitros, diazos, sulfoxides, sulfonyls, sulfonicacids, sulfamides, sulfonamides, sulfamic esters, aldehydes, ketones,carboxylic acids, esters, amides, amidines, formadines, amino acids,acetylenes, carbamates, lactones, lactams, glucosides, gluconurides,sulfones, ketals, acetals, thioketals, oximes, oxamic acids, oxamicesters, etc., and combinations of these groups. Substituent groupsbearing reactive functionalities may be protected or unprotected, as iswell-known in the art.

In one illustrative embodiment, the 2,4-pyrimidinediamine compounds ofthe invention are compounds according to structural formula (I):

including salts, hydrates, solvates and N-oxides thereof, wherein:

L¹ and L² are each, independently of one another, selected from thegroup consisting of a direct bond and a linker;

R² is selected from the group consisting of (C1-C6) alkyl optionallysubstituted with one or more of the same or different R⁸ groups, (C3-C8)cycloalkyl optionally substituted with one or more of the same ordifferent R⁸ groups, cyclohexyl optionally substituted with one or moreof the same or different R⁸ groups, 3-8 membered cycloheteroalkyloptionally substituted with one or more of the same or different R⁸groups, (C5-C15) aryl optionally substituted with one or more of thesame or different R⁸ groups, phenyl optionally substituted with one ormore of the same or different R⁸ groups and 5-15 membered heteroaryloptionally substituted with one or more of the same or different R⁸groups;

R⁴ is selected from the group consisting of hydrogen, (C1-C6) alkyloptionally substituted with one or more of the same or different R⁸groups, (C3-C8) cycloalkyl optionally substituted with one or more ofthe same or different R⁸ groups, cyclohexyl optionally substituted withone or more of the same or different R⁸ groups, 3-8 memberedcycloheteroalkyl optionally substituted with one or more of the same ordifferent R⁸ groups, (C5-C15) aryl optionally substituted with one ormore of the same or different R⁸ groups, phenyl optionally substitutedwith one or more of the same or different R⁸ groups and 5-15 memberedheteroaryl optionally substituted with one or more of the same ordifferent R⁸ groups;

R⁵ is selected from the group consisting of R⁶, (C1-C6) alkyl optionallysubstituted with one or more of the same or different R⁸ groups, (C1-C4)alkanyl optionally substituted with one or more of the same or differentR⁸ groups, (C2-C4) alkenyl optionally substituted with one or more ofthe same or different R⁸ groups and (C2-C4) alkynyl optionallysubstituted with one or more of the same or different R⁸ groups;

each R⁶ is independently selected from the group consisting of hydrogen,an electronegative group, —OR^(d), —SR^(d), (C1-C3) haloalkyloxy,(C1-C3) perhaloalkyloxy, —NR^(c)R^(c), halogen, (C1-C3) haloalkyl,(C1-C3) perhaloalkyl, —CF₃, —CH₂CF₃, —CF₂CF₃, —CN, —NC, —OCN, —SCN, —NO,—NO₂, —N₃, —S(O)R^(d), —S(O)₂R^(d), —S(O)₂OR^(d), —S(O)NR^(c)R^(c);—S(O)₂NR^(c)R^(c), —OS(O)R^(d), —OS(O)₂R^(d), —OS(O)₂OR^(d),—OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d),—C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c), —OC(O)R^(d), —SC(O)R^(d),—OC(O)OR^(d), —SC(O)OR^(d), —OC(O)NR^(c)R^(c), —SC(O)NR^(c)R^(c),—OC(NH)NR^(c)R^(c), —SC(NH)NR^(c)R^(c), —[NHC(O)]_(n)R^(d),—[NHC(O)]_(n)OR^(d), —[NHC(O)]_(n)NR^(c)R^(c) and—[NHC(NH)]_(n)NR^(c)R^(c), (C5-C10) aryl optionally substituted with oneor more of the same or different R⁸ groups, phenyl optionallysubstituted with one or more of the same or different R⁸ groups,(C6-C16) arylalkyl optionally substituted with one or more of the sameor different R⁸ groups, 5-10 membered heteroaryl optionally substitutedwith one or more of the same or different R⁸ groups and 6-16 memberedheteroarylalkyl optionally substituted with one or more of the same ordifferent R⁸ groups;

R⁸ is selected from the group consisting of R^(a), R^(b), R^(a)substituted with one or more of the same or different R^(a) or R^(b),—OR^(a) substituted with one or more of the same or different R^(a) orR^(b), —B(OR^(a))₂, —B(NR^(c)R^(c))₂, —(CH₂)_(m)—R^(b),—(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—R^(b), —S—(CH₂)_(m)—R^(b),—O—CHR^(a)R^(b), —O—CR^(a)(R^(b))₂, —O—(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)—CH[(CH₂)_(m)R^(b)]R^(b), —S—(CHR^(a))_(m)—R^(b),—C(O)NH—(CH₂)_(m)—R^(b), —C(O)NH—(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),—S—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),—O—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b),—S—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b), —NH—(CH₂)_(m)—R^(b),—NH—(CHR^(a))_(m)—R^(b), —NH[(CH₂)_(m)R^(b)], —N[(CH₂)_(m)R^(b)]₂,—NH—C(O)—NH—(CH₂)_(m)—R^(b), —NH—C(O)—(CH₂)_(m)—CHR^(b)R^(b) and—NH—(CH₂)_(m)—C(O)—NH—(CH₂)_(m)—R^(b);

each R^(a) is independently selected from the group consisting ofhydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl,piperazinyl, homopiperazinyl, piperidinyl, 4-11 memberedcycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 memberedheteroarylalkyl;

each R^(b) is a suitable group independently selected from the groupconsisting of ═O, —OR^(d), (C1-C3) haloalkyloxy, —OCF₃, ═S, —SR^(d),═NR^(d), ═NOR^(d), —NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)R^(d), —S(O)₂R^(d), —S(O)₂OR^(d),—S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(d), —OS(O)₂R^(d),—OS(O)₂OR^(d), —OS(O)₂NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d),—C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c), —C(NR^(a))NR^(c)R^(c),—C(NOH)R^(a), —C(NOH)NR^(c)R^(c), —OC(O)R^(d), —OC(O)OR^(d),—OC(O)NR^(c)R^(c), —OC(NH)NR^(c)R^(c), —OC(NR^(a))NR^(c)R^(c),—[NHC(O)]_(n)R^(d), —[NR^(a)C(O)]_(n)R^(d), —[NHC(O)]_(n)OR,—[NR^(a)C(O)]_(n)OR^(d), —[NHC(O)]; NR^(c)R^(c),—[NR^(a)C(O)]_(n)NR^(c)R^(c), —[NHC(NH)]_(n)NR^(c)R^(c) and—[NR^(a)C(NR^(a))]_(n)NR^(c)R^(c);

each R^(c) is independently a protecting group or R^(a), or,alternatively, each R^(c) is taken together with the nitrogen atom towhich it is bonded to form a 5 to 8-membered cycloheteroalkyl orheteroaryl which may optionally include one or more of the same ordifferent additional heteroatoms and which may optionally be substitutedwith one or more of the same or different R^(a) or suitable R^(b)groups;

each R^(d) is independently a protecting group or R^(a);

each m is independently an integer from 1 to 3; and

each n is independently an integer from 0 to 3.

In another aspect, the present invention provides prodrugs of the2,4-pyrimidinediamine compounds. Such prodrugs may be active in theirprodrug form, or may be inactive until converted under physiological orother conditions of use to an active drug form. In the prodrugs of theinvention, one or more functional groups of the 2,4-pyrimidinediaminecompounds are included in promoieties that cleave from the moleculeunder the conditions of use, typically by way of hydrolysis, enzymaticcleavage or some other cleavage mechanism, to yield the functionalgroups. For example, primary or secondary amino groups may be includedin an amide promoiety that cleaves under conditions of use to generatethe primary or secondary amino group. Thus, the prodrugs of theinvention include special types of protecting groups, termed“progroups,” masking one or more functional groups of the2,4-pyrimidinediamine compounds that cleave under the conditions of useto yield an active 2,4-pyrimidinediamine drug compound. Functionalgroups within the 2,4-pyrimidinediamine compounds that may be maskedwith progroups for inclusion in a promoiety include, but are not limitedto, amines (primary and secondary), hydroxyls, sulfanyls (thiols),carboxyls, carbonyls, phenols, catechols, diols, alkynes, phosphates,etc. Myriad progroups suitable for masking such functional groups toyield promoieties that are cleavable under the desired conditions of useare known in the art. All of these progroups, alone or in combinations,may be included in the prodrugs of the invention. Specific examples ofpromoieties that yield primary or secondary amine groups that can beincluded in the prodrugs of the invention include, but are not limitedto amides, carbamates, imines, ureas, phosphenyls, phosphoryls andsulfenyls. Specific examples of promoieties that yield sulfanyl groupsthat can be included in the prodrugs of the invention include, but arenot limited to, thioethers, for example S-methyl derivatives (monothio,dithio, oxythio, aminothio acetals), silyl thioethers, thioesters,thiocarbonates, thiocarbamates, asymmetrical disulfides, etc. Specificexamples of promoieties that cleave to yield hydroxyl groups that can beincluded in the prodrugs of the invention include, but are not limitedto, sulfonates, esters and carbonates. Specific examples of promoietiesthat yield carboxyl groups that can be included in the prodrugs of theinvention included, but are not limited to, esters (including silylesters, oxamic acid esters and thioesters), amides and hydrazides.

In one illustrative embodiment, the prodrugs of the invention arecompounds according to structural formula (I) in which the protectinggroup of R^(c) and R^(d) is a progroup.

Replacing the hydrogens attached to N2 and N4 in the2,4-pyrimidinediamines of structural formula (I) with substituentsadversely affects the activity of the compounds. However, as will beappreciated by skilled artisans, these nitrogens may be included inpromoieties that, under conditions of use, cleave to yield2,4-pyrimidinediamines according to structural formula (I). Thus, inanother illustrative embodiment, the prodrugs of the invention arecompounds according to structural formula (II):

including salts, hydrates, solvates and N-oxides thereof, wherein:

R², R⁴, R⁵, R⁶, L¹ and L² are as previously defined for structuralformula (I); and

R^(2b) and R^(4b) are each, independently of one another, a progroup.

In another aspect, the present invention provides compositionscomprising one or more compounds and/or prodrugs of the invention and anappropriate carrier, excipient or diluent. The exact nature of thecarrier, excipient or diluent will depend upon the desired use for thecomposition, and may range from being suitable or acceptable forveterinary uses to being suitable or acceptable for human use.

In still another aspect, the present invention provides intermediatesuseful for synthesizing the 2,4-pyrimidinediamine compounds and prodrugsof the invention. In one embodiment, the intermediates are4-pyrimidineamines according to structural formula (III):

including salts, hydrates, solvates and N-oxides thereof, wherein R⁴,R⁵, R⁶ and L² are as previously defined for structural formula (I); LGis a leaving group such as, for example, —S(O)₂Me, —SMe or halo (e.g.,F, Cl, Br, I); and R^(4c) is hydrogen or a progroup.

In another embodiment, the intermediates are 2-pyrimidineaminesaccording to structural formula (IV):

including salts, hydrates, solvates and N-oxides thereof, wherein R²,R⁵, R⁶ and L¹ are as previously defined for structural formula (I); LGis a leaving group, such as, for example, —S(O)₂Me, —SMe or halo (e.g.,F, Cl, Br, I) and R^(2c) is hydrogen or a progroup.

In yet another embodiment, the intermediates are 4-amino- or4-hydroxy-2-pyrimidineamines according to structural formula (V):

including salts, hydrates, solvates and N-oxides thereof, wherein R²,R⁵, R⁶ and L¹ are as previously defined for structural formula (I), R⁷is an amino or hydroxyl group and R^(2c) is hydrogen or a progroup.

In another embodiment, the intermediates are N4-substituted cytosinesaccording to structural formula (VI):

including salts, hydrates, solvates and N-oxides thereof, wherein R⁴,R⁵, R⁶ and L² are as previously defined for structural formula (I) andR^(4c) is hydrogen or a progroup.

In yet another aspect, the present invention provides methods ofsynthesizing the 2,4-pyrimidinediamine compounds and prodrugs of theinvention. In one embodiment, the method involves reacting a4-pyrimidineamine according to structural formula (III) with an amine ofthe formula HR^(2c)N-L¹-R², where L¹, R² and R^(2c) are as previouslydefined for structural formula (IV) to yield a 2,4-pyrimidinediamineaccording to structural formula (I) or a prodrug according to structuralformula (II).

In another embodiment, the method involves reacting a 2-pyrimidineamineaccording to structural formula (IV) with an amine of the formulaR⁴-L²-NHR^(4c) where L⁴, R⁴ and R^(4c) are as previously defined forstructural formula (III) to yield a 2,4-pyrimidinediamine according tostructural formula (I) or a prodrug according to structural formula(II).

In yet another embodiment, the method involves reacting a4-amino-2-pyrimidineamine according to structural formula (V) (in whichR⁷ is an amino group) with an amine of the formula R⁴-L²-NHR^(4c), whereL², R⁴ and R^(4c) are as defined for structural formula (III), to yielda 2,4-pyrimidinediamine according to structural formula (I) or a prodrugaccording to structural formula (II). Alternatively, the4-amino-2-pyrimidineamine may be reacted with a compound of the formulaR⁴-L²-LG, where R⁴ and L² are as previously defined for structuralformula (I) and LG is a leaving group.

In still another embodiment, the method involves halogenating a4-hydroxy-2-pyrimidineamine according to structural formula (V) (R⁷ is ahydroxyl group) to yield a 2-pyrimidineamine according to structuralformula (IV) and reacting this pyrimidineamine with an appropriateamine, as described above.

In yet another embodiment, the method involves halogenating anN4-substituted cytosine according to structural formula (VI) to yield a4-pyrimidineamine according to structural formula (III) and reactingthis pyrimidineamine with an appropriate amine, as described above.

The 2,4-pyrimidinediamine compounds of the invention are potentinhibitors of degranulation of immune cells, such as mast, basophil,neutrophil and/or eosinophil cells. Thus, in still another aspect, thepresent invention provides methods of regulating, and in particularinhibiting, degranulation of such cells. The method generally involvescontacting a cell that degranulates with an amount of a2,4-pyrimidinediamine compound or prodrug of the invention, or anacceptable salt, hydrate, solvate, N-oxide and/or composition thereof,effective to regulate or inhibit degranulation of the cell. The methodmay be practiced in in vitro contexts or in in vivo contexts as atherapeutic approach towards the treatment or prevention of diseasescharacterized by, caused by or associated with cellular degranulation.

While not intending to be bound by any theory of operation, biochemicaldata confirm that the 2,4-pyrimidinediamine compounds exert theirdegranulation inhibitory effect, at least in part, by blocking orinhibiting the signal transduction cascade(s) initiated by crosslinkingof the high affinity Fc receptors for IgE (“FcεRI”) and/or IgG(“FcγRI”). Indeed, the 2,4-pyrimidinediamine compounds are potentinhibitors of both FcεRI-mediated and FcγRI-mediated degranulation. As aconsequence, the 2,4-pyrimidine compounds may be used to inhibit theseFc receptor signaling cascades in any cell type expressing such FcεRIand/or FcγRI receptors including but not limited to macrophages, mast,basophil, neutrophil and/or eosinophil cells.

The methods also permit the regulation of, and in particular theinhibition of, downstream processes that result as a consequence ofactivating such Fc receptor signaling cascade(s). Such downstreamprocesses include, but are not limited to, FcεRI-mediated and/orFcγRI-mediated degranulation, cytokine production and/or the productionand/or release of lipid mediators such as leukotrienes andprostaglandins. The method generally involves contacting a cellexpressing an Fc receptor, such as one of the cell types discussedabove, with an amount of a 2,4-pyrimidinediamine compound or prodrug ofthe invention, or an acceptable salt, hydrate, solvent, N-oxide and/orcomposition thereof, effective to regulate or inhibit the Fc receptorsignaling cascade and/or a downstream process effected by the activationof this signaling cascade. The method may be practiced in in vitrocontexts or in in vivo contexts as a therapeutic approach towards thetreatment or prevention of diseases characterized by, caused by orassociated with the Fc receptor signaling cascade, such as diseaseseffected by the release of granule specific chemical mediators upondegranulation, the release and/or synthesis of cytokines and/or therelease and/or synthesis of lipid mediators such as leukotrienes andprostaglandins.

In yet another aspect, the present invention provides methods oftreating and/or preventing diseases characterized by, caused by orassociated with the release of chemical mediators as a consequence ofactivating Fc receptor signaling cascades, such as FcεRI and/orFcγRI-signaling cascades. The methods may be practiced in animals inveterinary contexts or in humans. The methods generally involveadministering to an animal subject or human an amount of a2,4-pyrimidinediamine compound or prodrug of the invention, or anacceptable salt, hydrate, solvate, N-oxide and/or composition thereof,effective to treat or prevent the disease. As discussed previously,activation of the FcεRI or FcγRI receptor signaling cascade in certainimmune cells leads to the release and/or synthesis of a variety ofchemical substances that are pharmacological mediators of a wide varietyof diseases. Any of these diseases may be treated or prevented accordingto the methods of the invention.

For example, in mast cells and basophil cells, activation of the FcεRIor FcγRI signaling cascade leads to the immediate (i.e., within 1-3 min.of receptor activation) release of preformed mediators of atopic and/orType I hypersensitivity reactions (e.g., histamine, proteases such astryptase, etc.) via the degranulation process. Such atopic or Type Ihypersensitivity reactions include, but are not limited to, anaphylacticreactions to environmental and other allergens (e.g., pollens, insectand/or animal venoms, foods, drugs, contrast dyes, etc.), anaphylactoidreactions, hay fever, allergic conjunctivitis, allergic rhinitis,allergic asthma, atopic dermatitis, eczema, urticaria, mucosaldisorders, tissue disorders and certain gastrointestinal disorders.

The immediate release of the preformed mediators via degranulation isfollowed by the release and/or synthesis of a variety of other chemicalmediators, including, among other things, platelet activating factor(PAF), prostaglandins and leukotrienes (e.g., LTC4) and the de novosynthesis and release of cytokines such as TNFα, IL-4, IL-5, IL-6,IL-13, etc. The first of these two processes occurs approximately 3-30min. following receptor activation; the latter approximately 30 min.-7hrs. following receptor activation. These “late stage” mediators arethought to be in part responsible for the chronic symptoms of theabove-listed atopic and Type I hypersensitivity reactions, and inaddition are chemical mediators of inflammation and inflammatorydiseases (e.g., osteoarthritis, inflammatory bowel disease, ulcerativecolitis, Crohn's disease, idiopathic inflammatory bowel disease,irritable bowel syndrome, spastic colon, etc.), low grade scarring(e.g., scleroderma, increased fibrosis, keloids, post-surgical scars,pulmonary fibrosis, vascular spasms, migraine, reperfusion injury andpost myocardial infarction), and sicca complex or syndrome. All of thesediseases may be treated or prevented according to the methods of theinvention.

Additional diseases which can be treated or prevented according to themethods of the invention include diseases associated with basophil celland/or mast cell pathology. Examples of such diseases include, but arenot limited to, diseases of the skin such as scleroderma, cardiacdiseases such as post myocardial infarction, pulmonary diseases such aspulmonary muscle changes or remodeling and chronic obstructive pulmonarydisease (COPD) and diseases of the gut such as inflammatory bowelsyndrome (spastic colon).

The 2,4-pyrimidinediamine compounds of the invention are also potentinhibitors of the tyrosine kinase Syk kinase. Thus, in still anotheraspect, the present invention provides methods of regulating, and inparticular inhibiting, Syk kinase activity. The method generallyinvolves contacting a Syk kinase or a cell comprising a Syk kinase withan amount of a 2,4-pyrimidinediamine compound or prodrug of theinvention, or an acceptable salt, hydrate, solvate, N-oxide and/orcomposition thereof, effective to regulate or inhibit Syk kinaseactivity. In one embodiment, the Syk kinase is an isolated orrecombinant Syk kinase. In another embodiment, the Syk kinase is anendogenous or recombinant Syk kinase expressed by a cell, for example amast cell or a basophil cell. The method may be practiced in in vitrocontexts or in in vivo contexts as a therapeutic approach towards thetreatment or prevention of diseases characterized by, caused by orassociated with Syk kinase activity.

While not intending to be bound by any particular theory of operation,it is believed that the 2,4-pyrimdinediamine compounds of the inventioninhibit cellular degranulation and/or the release of other chemicalmediators primarily by inhibiting Syk kinase that gets activated throughthe gamma chain homodimer of FcεRI (see, e.g., FIG. 2). This gamma chainhomodimer is shared by other Fc receptors, including FcγRI, FcγRIII andFcαRI. For all of these receptors, intracellular signal transduction ismediated by the common gamma chain homodimer. Binding and aggregation ofthose receptors results in the recruitment and activation of tyrosinekinases such as Syk kinase. As a consequence of these common signalingactivities, the 2,4-pyrimidinediamine compounds described herein may beused to regulate, and in particular inhibit, the signaling cascades ofFc receptors having this gamma chain homodimer, such as FcεRI, FcγRI,FcγRIII and FcαRI, as well as the cellular responses elicited throughthese receptors.

Syk kinase is known to play a critical role in other signaling cascades.For example, Syk kinase is an effector of B-cell receptor (BCR)signaling (Turner et al., 2000, Immunology Today 21:148-154) and is anessential component of integrin beta(1), beta(2) and beta(3) signalingin neutrophils (Mocsai et al., 2002, Immunity 16:547-558). As the2,4-pyrimidinediamine compounds described herein are potent inhibitorsof Syk kinase, they can be used to regulate, and in particular inhibit,any signaling cascade where Syk plays a role, such as, fore example, theFc receptor, BCR and integrin signaling cascades, as well as thecellular responses elicited through these signaling cascades. Theparticular cellular response regulated or inhibited will depend, inpart, on the specific cell type and receptor signaling cascade, as iswell known in the art. Non-limiting examples of cellular responses thatmay be regulated or inhibited with the 2,4-pyrimidinediamine compoundsinclude a respiratory burst, cellular adhesion, cellular degranulation,cell spreading, cell migration, phagocytosis (e.g., in macrophages),calcium ion flux (e.g., in mast, basophil, neutrophil, eosinophil andB-cells), platelet aggregation, and cell maturation (e.g., in B-cells).

Thus, in another aspect, the present invention provides methods ofregulating, and in particular inhibiting, signal transduction cascadesin which Syk plays a role. The method generally involves contacting aSyk-dependent receptor or a cell expressing a Syk-dependent receptorwith an amount of a 2,4-pyrimidinediamine compound or prodrug of theinvention, or an acceptable salt, hydrate, solvate, N-oxide and/orcomposition thereof, effective to regulate or inhibit the signaltransduction cascade. The methods may also be used to regulate, and inparticular inhibit, downstream processes or cellular responses elicitedby activation of the particular Syk-dependent signal transductioncascade. The methods may be practiced to regulate any signaltransduction cascade where Syk is not known or later discovered to playa role. The methods may be practiced in in vitro contexts or in in vivocontexts as a therapeutic approach towards the treatment or preventionof diseases characterized by, caused by or associated with activation ofthe Syk-dependent signal transduction cascade. Non-limited examples ofsuch diseases include those previously discussed.

5. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 provides a cartoon illustrating allergen-induced production ofIgE and consequent release of preformed and other chemical mediatorsfrom mast cells;

FIG. 2 provides a cartoon illustrating the FcεR1 signal transductioncascade leading to degranulation of mast and/or basophil cells;

FIG. 3 provides a cartoon illustrating the putative points of action ofcompounds that selectively inhibit upstream FcεRI-mediated degranulationand compounds that inhibit both FcεRI-mediated and ionomycin-induceddegranulation;

FIG. 4 provides graphs illustrating the effects of certain2,4-pyrimidinediamine compounds, DMSO (control) and ionomycin on Ca²⁺flux in CHMC cells;

FIG. 5 provides graphs illustrating the immediacy of the inhibitoryactivity of compounds R921218 and R926495;

FIG. 6 provides a graph illustrating the effect of washout on theinhibitory activity of compounds R921218 and R921302;

FIG. 7 provides data showing that varying concentrations of compoundsR921218 (A) and R921219 (B) inhibit phosporylation of various proteinsdownstream of Syk kinase in the IgE receptor signal transduction cascadein activated BMMC cells;

FIG. 8 provides data showing dose responsive inhibition of Syk kinasephosphorylation of an endogenous substrate (LAT) and a peptide substratein the presence of increasing concentrations of compounds R921218 (X),R921219 (Y) and R921304 (Z);

FIG. 9 provides data showing that the inhibition of Syk kinase bycompound R921219 is ATP competitive;

FIG. 10 provides data showing that varying concentrations of compoundsR921219 (A) and R218218 (B) inhibit phosphorylation of proteinsdownstream of Syk kinase, but not LYN kinase, in the FcεRI signaltransduction cascade in activated CHMC cells; also shown is inhibitionof phosphorylation of proteins downstream of LYN kinase but not Sykkinase, in the presence of a known LYN kinase inhibitor (PP2); and

FIGS. 11A-D provide data showing inhibition of phosphorylation ofproteins downstream of Syk kinase in the FcεRI signal transductioncascade in BMMC cells.

6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 6.1 Definitions

As used herein, the following terms are intended to have the followingmeanings:

“Alkyl” by itself or as part of another substituent refers to asaturated or unsaturated branched, straight-chain or cyclic monovalenthydrocarbon radical having the stated number of carbon atoms (i.e.,C1-C6 means one to six carbon atoms) that is derived by the removal ofone hydrogen atom from a single carbon atom of a parent alkane, alkeneor alkyne. Typical alkyl groups include, but are not limited to, methyl;ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl,propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl,prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl,butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Wherespecific levels of saturation are intended, the nomenclature “alkanyl,”“alkenyl” and/or “alkynyl” is used, as defined below. In preferredembodiments, the alkyl groups are (C1-C6) alkyl.

“Alkanyl” by itself or as part of another substituent refers to asaturated branched, straight-chain or cyclic alkyl derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkane. Typical alkanyl groups include, but are not limited to,methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl(isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl,butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like. Inpreferred embodiments, the alkanyl groups are (C1-C6) alkanyl.

“Alkenyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl having at least onecarbon-carbon double bond derived by the removal of one hydrogen atomfrom a single carbon atom of a parent alkene. The group may be in eitherthe cis or trans conformation about the double bond(s). Typical alkenylgroups include, but are not limited to, ethenyl; propenyls such asprop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl,cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such asbut-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.;and the like. In preferred embodiments, the alkenyl group is (C2-C6)alkenyl.

“Alkynyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl having at least onecarbon-carbon triple bond derived by the removal of one hydrogen atomfrom a single carbon atom of a parent alkyne. Typical alkynyl groupsinclude, but are not limited to, ethynyl; propynyls such asprop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. In preferredembodiments, the alkynyl group is (C2-C6) alkynyl.

“Alkyldiyl” by itself or as part of another substituent refers to asaturated or unsaturated, branched, straight-chain or cyclic divalenthydrocarbon group having the stated number of carbon atoms (i.e., C1-C6means from one to six carbon atoms) derived by the removal of onehydrogen atom from each of two different carbon atoms of a parentalkane, alkene or alkyne, or by the removal of two hydrogen atoms from asingle carbon atom of a parent alkane, alkene or alkyne. The twomonovalent radical centers or each valency of the divalent radicalcenter can form bonds with the same or different atoms. Typicalalkyldiyl groups include, but are not limited to, methandiyl; ethyldiylssuch as ethan-1,1-diyl, ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl;propyldiyls such as propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl,propan-1,3-diyl, cyclopropan-1,1-diyl, cyclopropan-1,2-diyl,prop-1-en-1,1-diyl, prop-1-en-1,2-diyl, prop-2-en-1,2-diyl,prop-1-en-1,3-diyl, cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl,cycloprop-2-en-1,1-diyl, prop-1-yn-1,3-diyl, etc.; butyldiyls such as,butan-1,1-diyl, butan-1,2-diyl, butan-1,3-diyl, butan-1,4-diyl,butan-2,2-diyl, 2-methyl-propan-1,1-diyl, 2-methyl-propan-1,2-diyl,cyclobutan-1,1-diyl; cyclobutan-1,2-diyl, cyclobutan-1,3-diyl,but-1-en-1,1-diyl, but-1-en-1,2-diyl, but-1-en-1,3-diyl,but-1-en-1,4-diyl, 2-methyl-prop-1-en-1,1-diyl,2-methanylidene-propan-1,1-diyl, buta-1,3-dien-1,1-diyl,buta-1,3-dien-1,2-diyl, buta-1,3-dien-1,3-diyl, buta-1,3-dien-1,4-diyl,cyclobut-1-en-1,2-diyl, cyclobut-1-en-1,3-diyl, cyclobut-2-en-1,2-diyl,cyclobuta-1,3-dien-1,2-diyl, cyclobuta-1,3-dien-1,3-diyl,but-1-yn-1,3-diyl, but-1-yn-1,4-diyl, buta-1,3-diyn-1,4-diyl, etc.; andthe like. Where specific levels of saturation are intended, thenomenclature alkanyldiyl, alkenyldiyl and/or alkynyldiyl is used. Whereit is specifically intended that the two valencies are on the samecarbon atom, the nomenclature “alkylidene” is used. In preferredembodiments, the alkyldiyl group is (C1-C6) alkyldiyl. Also preferredare saturated acyclic alkanyldiyl groups in which the radical centersare at the terminal carbons, e.g., methandiyl (methano); ethan-1,2-diyl(ethano); propan-1,3-diyl (propano); butan-1,4-diyl (butano); and thelike (also referred to as alkylenos, defined infra).

“Alkyleno” by itself or as part of another substituent refers to astraight-chain saturated or unsaturated alkyldiyl group having twoterminal monovalent radical centers derived by the removal of onehydrogen atom from each of the two terminal carbon atoms ofstraight-chain parent alkane, alkene or alkyne. The locant of a doublebond or triple bond, if present, in a particular alkyleno is indicatedin square brackets. Typical alkyleno groups include, but are not limitedto, methano; ethylenos such as ethano, etheno, ethyno; propylenos suchas propano, prop[1]eno, propa[1,2]dieno, prop[1]yno, etc.; butylenossuch as butano, but[1]eno, but[2]eno, buta[1,3]dieno, but[1]yno,but[2]yno, buta[1,3]diyno, etc.; and the like. Where specific levels ofsaturation are intended, the nomenclature alkano, alkeno and/or alkynois used. In preferred embodiments, the alkyleno group is (C1-C6) or(C1-C3) alkyleno. Also preferred are straight-chain saturated alkanogroups, e.g., methano, ethano, propano, butano, and the like.

“Heteroalkyl,” Heteroalkanyl,” Heteroalkenyl,” Heteroalkynyl,”Heteroalkyldiyl” and “Heteroalkyleno” by themselves or as part ofanother substituent refer to alkyl, alkanyl, alkenyl, alkynyl, alkyldiyland alkyleno groups, respectively, in which one or more of the carbonatoms are each independently replaced with the same or differentheteratoms or heteroatomic groups. Typical heteroatoms and/orheteroatomic groups which can replace the carbon atoms include, but arenot limited to, —O—, —S—, —S—O—, —NR′—, —PH—, —S(O)—, —S(O)₂—, —S(O)NR′—, —S(O)₂NR′—, and the like, including combinations thereof, whereeach R′ is independently hydrogen or (C1-C6) alkyl.

“Cycloalkyl” and “Heterocycloalkyl” by themselves or as part of anothersubstituent refer to cyclic versions of “alkyl” and “heteroalkyl”groups, respectively. For heteroalkyl groups, a heteroatom can occupythe position that is attached to the remainder of the molecule. Typicalcycloalkyl groups include, but are not limited to, cyclopropyl;cyclobutyls such as cyclobutanyl and cyclobutenyl; cyclopentyls such ascyclopentanyl and cyclopentenyl; cyclohexyls such as cyclohexanyl andcyclohexenyl; and the like. Typical heterocycloalkyl groups include, butare not limited to, tetrahydrofuranyl (e.g., tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, etc.), piperidinyl (e.g., piperidin-1-yl,piperidin-2-yl, etc.), morpholinyl (e.g., morpholin-3-yl,morpholin-4-yl, etc.), piperazinyl (e.g., piperazin-1-yl,piperazin-2-yl, etc.), and the like.

“Acyclic Heteroatomic Bridge” refers to a divalent bridge in which thebackbone atoms are exclusively heteroatoms and/or heteroatomic groups.Typical acyclic heteroatomic bridges include, but are not limited to,—O—, —S—, —S—O—, —NR′—, —PH—, —S(O)—, —S(O)₂—, —S(O) NR′—, —S(O)₂NR′—,and the like, including combinations thereof, where each R′ isindependently hydrogen or (C1-C6) alkyl.

“Parent Aromatic Ring System” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more of the rings arearomatic and one or more of the rings are saturated or unsaturated, suchas, for example, fluorene, indane, indene, phenalene,tetrahydronaphthalene, etc. Typical parent aromatic ring systemsinclude, but are not limited to, aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, tetrahydronaphthalene, triphenylene, trinaphthalene, and thelike, as well as the various hydro isomers thereof.

“Aryl” by itself or as part of another substituent refers to amonovalent aromatic hydrocarbon group having the stated number of carbonatoms (i.e., C5-C15 means from 5 to 15 carbon atoms) derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene, and the like, as well as thevarious hydro isomers thereof. In preferred embodiments, the aryl groupis (C5-C15) aryl, with (C5-C10) being even more preferred. Particularlypreferred aryls are cyclopentadienyl, phenyl and naphthyl.

“Arylaryl” by itself or as part of another substituent refers to amonovalent hydrocarbon group derived by the removal of one hydrogen atomfrom a single carbon atom of a ring system in which two or moreidentical or non-identical parent aromatic ring systems are joineddirectly together by a single bond, where the number of such direct ringjunctions is one less than the number of parent aromatic ring systemsinvolved. Typical arylaryl groups include, but are not limited to,biphenyl, triphenyl, phenyl-naphthyl, binaphthyl, biphenyl-naphthyl, andthe like. Where the number of carbon atoms in an arylaryl group arespecified, the numbers refer to the carbon atoms comprising each parentaromatic ring. For example, (C5-C15) arylaryl is an arylaryl group inwhich each aromatic ring comprises from 5 to 15 carbons, e.g., biphenyl,triphenyl, binaphthyl, phenylnaphthyl, etc. Preferably, each parentaromatic ring system of an arylaryl group is independently a (C5-C15)aromatic, more preferably a (C5-C10) aromatic. Also preferred arearylaryl groups in which all of the parent aromatic ring systems areidentical, e.g., biphenyl, triphenyl, binaphthyl, trinaphthyl, etc.

“Biaryl” by itself or as part of another substituent refers to anarylaryl group having two identical parent aromatic systems joineddirectly together by a single bond. Typical biaryl groups include, butare not limited to, biphenyl, binaphthyl, bianthracyl, and the like.Preferably, the aromatic ring systems are (C5-C15) aromatic rings, morepreferably (C5-C10) aromatic rings. A particularly preferred biarylgroup is biphenyl.

“Arylalkyl” by itself or as part of another substituent refers to anacyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced withan aryl group. Typical arylalkyl groups include, but are not limited to,benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl,2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. Where specific alkyl moietiesare intended, the nomenclature arylalkanyl, arylakenyl and/orarylalkynyl is used. In preferred embodiments, the arylalkyl group is(C6-C21) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of thearylalkyl group is (C1-C6) and the aryl moiety is (C5-C15). Inparticularly preferred embodiments the arylalkyl group is (C6-C13),e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is(C1-C3) and the aryl moiety is (C5-C10).

“Parent Heteroaromatic Ring System” refers to a parent aromatic ringsystem in which one or more carbon atoms are each independently replacedwith the same or different heteroatoms or heteroatomic groups. Typicalheteroatoms or heteroatomic groups to replace the carbon atoms include,but are not limited to, N, NH, P, O, S, S(O), S(O)₂, Si, etc.Specifically included within the definition of “parent heteroaromaticring systems” are fused ring systems in which one or more of the ringsare aromatic and one or more of the rings are saturated or unsaturated,such as, for example, benzodioxan, benzofuran, chromane, chromene,indole, indoline, xanthene, etc. Also included in the definitionof“parent heteroaromatic ring system” are those recognized rings thatinclude common substituents, such as, for example, benzopyrone and1-methyl-1,2,3,4-tetrazole. Specifically excluded from the definition of“parent heteroaromatic ring system” are benzene rings fused to cyclicpolyalkylene glycols such as cyclic polyethylene glycols. Typical parentheteroaromatic ring systems include, but are not limited to, acridine,benzimidazole, benzisoxazole, benzodioxan, benzodioxole, benzofuran,benzopyrone, benzothiadiazole, benzothiazole, benzotriazole,benzoxaxine, benzoxazole, benzoxazoline, carbazole, O-carboline,chromane, chromene, cinnoline, furan, imidazole, indazole, indole,indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like.

“Heteroaryl” by itself or as part of another substituent refers to amonovalent heteroaromatic group having the stated number of ring atoms(e.g., “5-14 membered” means from 5 to 14 ring atoms) derived by theremoval of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, groups derived from acridine, benzimidazole,benzisoxazole, benzodioxan, benzodiaxole, benzofuran, benzopyrone,benzothiadiazole, benzothiazole, benzotriazole, benzoxazine,benzoxazole, benzoxazoline, carbazole, O-carboline, chromane, chromene,cinnoline, furan, imidazole, indazole, indole, indoline, indolizine,isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike, as well as the various hydro isomers thereof. In preferredembodiments, the heteroaryl group is a 5-14 membered heteroaryl, with5-10 membered heteroaryl being particularly preferred.

“Heteroaryl-Heteroaryl” by itself or as part of another substituentrefers to a monovalent heteroaromatic group derived by the removal ofone hydrogen atom from a single atom of a ring system in which two ormore identical or non-identical parent heteroaromatic ring systems arejoined directly together by a single bond, where the number of suchdirect ring junctions is one less than the number of parentheteroaromatic ring systems involved. Typical heteroaryl-heteroarylgroups include, but are not limited to, bipyridyl, tripyridyl,pyridylpurinyl, bipurinyl, etc. Where the number of atoms are specified,the numbers refer to the number of atoms comprising each parentheteroaromatic ring systems. For example, 5-15 memberedheteroaryl-heteroaryl is a heteroaryl-heteroaryl group in which eachparent heteroaromatic ring system comprises from 5 to 15 atoms, e.g.,bipyridyl, tripuridyl, etc. Preferably, each parent heteroaromatic ringsystem is independently a 5-15 membered heteroaromatic, more preferablya 5-10 membered heteroaromatic. Also preferred are heteroaryl-heteroarylgroups in which all of the parent heteroaromatic ring systems areidentical.

“Biheteroaryl” by itself or as part of another substituent refers to aheteroaryl-heteroaryl group having two identical parent heteroaromaticring systems joined directly together by a single bond. Typicalbiheteroaryl groups include, but are not limited to, bipyridyl,bipurinyl, biquinolinyl, and the like. Preferably, the heteroaromaticring systems are 5-15 membered heteroaromatic rings, more preferably5-10 membered heteroaromatic rings.

“Heteroarylalkyl” by itself or as part of another substituent refers toan acyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced with aheteroaryl group. Where specific alkyl moieties are intended, thenomenclature heteroarylalkanyl, heteroarylakenyl and/orheteroarylalkynyl is used. In preferred embodiments, the heteroarylalkylgroup is a 6-21 membered heteroarylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the heteroarylalkyl is (C1-C6) alkyl and theheteroaryl moiety is a 5-15-membered heteroaryl. In particularlypreferred embodiments, the heteroarylalkyl is a 6-13 memberedheteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety is (C1-C3)alkyl and the heteroaryl moiety is a 5-10 membered heteroaryl.

“Halogen” or “Halo” by themselves or as part of another substituent,unless otherwise stated, refer to fluoro, chloro, bromo and iodo.

“Haloalkyl” by itself or as part of another substituent refers to analkyl group in which one or more of the hydrogen atoms is replaced witha halogen. Thus, the term “haloalkyl” is meant to includemonohaloalkyls, dihaloalkyls, trihaloalkyls, etc. up to perhaloalkyls.For example, the expression “(C1-C2) haloalkyl” includes fluoromethyl,difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl,1,2-difluoroethyl, 1,1,1-trifluoroethyl, perfluoroethyl, etc.

The above-defined groups may include prefixes and/or suffixes that arecommonly used in the art to create additional well-recognizedsubstituent groups. As examples, “alkyloxy” or “alkoxy” refers to agroup of the formula —OR″, “alkylamine” refers to a group of the formula—NHR″ and “dialkylamine” refers to a group of the formula —NR″R″, whereeach R″ is independently an alkyl. As another example, “haloalkoxy” or“haloalkyloxy” refers to a group of the formula —OR′″, where R′″ is ahaloalkyl.

“Protecting group” refers to a group of atoms that, when attached to areactive functional group in a molecule, mask, reduce or prevent thereactivity of the functional group. Typically, a protecting group may beselectively removed as desired during the course of a synthesis.Examples of protecting groups can be found in Greene and Wuts,Protective Groups in Organic Chemistry, 3^(rd) Ed., 1999, John Wiley &Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods,Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative aminoprotecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“TES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxyl protecting groupsinclude, but are not limited to, those where the hydroxyl group iseither acylated or alkylated such as benzyl and trityl ethers, as wellas alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g.,TMS or TIPPS groups) and allyl ethers.

“Prodrug” refers to a derivative of an active 2,4-pyrimidinediaminecompound (drug) that requires a transformation under the conditions ofuse, such as within the body, to release the active2,4-pyrimidinediamine drug. Prodrugs are frequently, but notnecessarily, pharmacologically inactive until converted into the activedrug. Prodrugs are typically obtained by masking a functional group inthe 2,4-pyrimidinediamine drug believed to be in part required foractivity with a progroup (defined below) to form a promoiety whichundergoes a transformation, such as cleavage, under the specifiedconditions of use to release the functional group, and hence the active2,4-pyrimidinediamine drug. The cleavage of the promoiety may proceedspontaneously, such as by way of a hydrolysis reaction, or it may becatalyzed or induced by another agent, such as by an enzyme, by light,by acid or base, or by a change of or exposure to a physical orenvironmental parameter, such as a change of temperature. The agent maybe endogenous to the conditions of use, such as an enzyme present in thecells to which the prodrug is administered or the acidic conditions ofthe stomach, or it may be supplied exogenously.

A wide variety of progroups, as well as the resultant promoieties,suitable for masking functional groups in the active2,4-pyrimidinediamines compounds to yield prodrugs are well-known in theart. For example, a hydroxyl functional group may be masked as asulfonate, ester or carbonate promoiety, which may be hydrolyzed in vivoto provide the hydroxyl group. An amino functional group may be maskedas an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenylpromoiety, which may be hydrolyzed in vivo to provide the amino group. Acarboxyl group may be masked as an ester (including silyl esters andthioesters), amide or hydrazide promoiety, which may be hydrolyzed invivo to provide the carboxyl group. Other specific examples of suitableprogroups and their respective promoieties will be apparent to those ofskill in the art.

“Progroup” refers to a type of protecting group that, when used to maska functional group within an active 2,4-pyrimidinediamine drug to form apromoiety, converts the drug into a prodrug. Progroups are typicallyattached to the functional group of the drug via bonds that arecleavable under specified conditions of use. Thus, a progroup is thatportion of a promoiety that cleaves to release the functional groupunder the specified conditions of use. As a specific example, an amidepromoiety of the formula —NH—C(O)CH₃ comprises the progroup —C(O)CH₃.

“Fc Receptor” refers to a member of the family of cell surface moleculesthat binds the Fc portion (containing the specific constant region) ofan immunoglobulin. Each Fc receptor binds immunoglobulins of a specifictype. For example the Fcα receptor (“FcαR”) binds IgA, the FcεR bindsIgE and the FcγR binds IgG.

The FcαR family includes the polymeric Ig receptor involved inepithelial transport of IgA/IgM, the myeloid specific receptor RcαRI(also called CD89), the Fcα/μR and at least two alternative IgAreceptors (for a recent review see Monteiro & van de Winkel, 2003, Annu.Rev. Immunol, advanced e-publication. The FcαRI is expressed onneutrophils, eosinophils, moncytes/macrophages, dendritic cells andkupfer cells. The FcαRI includes one alpha chain and the FcεR gammahomodimer that bears an activation motif (ITAM) in the cytoplasmicdomain and phosphorylates Syk kinase.

The FcεR family includes two types, designated FcεRI and FcεRII (alsoknown as CD23). FcεRI is a high affinity receptor (binds IgE with anaffinity of about 10¹⁰M⁻¹) found on mast, basophil and eosinophil cellsthat anchors monomeric IgE to the cell surface. The FcεRI possesses onealpha chain, one beta chain and the gamma chain homodimer discussedabove. The FcεRII is a low affinity receptor expressed on mononuclearphagocytes, B lymphocytes, eosinophils and platelets. The FcεRIIcomprises a single polypeptide chain and does not include the gammachain homodimer.

The FcγR family includes three types, designated FcγRI (also known asCD64), FcγRII (also known as CD32) and FcγRIII (also known as CD16).FcγRI is a high affinity receptor (binds IgG1 with an affinity of10⁸M⁻¹) found on mast, basophil, mononuclear, neutrophil, eosinophil,deudritic and phagocyte cells that anchors nomomeric IgG to the cellsurface. The FcγRI includes one alpha chain and the gamma chain dimershared by FcαRI and FcεRI.

The FcγRII is a low affinity receptor expressed on neutrophils,monocytes, eosinophils, platelets and B lymphocytes. The FcγRII includesone alpha chain, and does not include the gamma chain homodimerdiscussed above.

The FcγRIII is a low affinity (bindes IgG1 with an affinity of 5×10⁵M⁻¹)expressed on NK, eosinophil, macrophage, neutrophil and mast cells. Itcomprises one alpha chain and the gamma homodimer shared by FcαRI, FcεRIand FcγRI.

Skilled artisans will recognize that the subunit structure and bindingproperties of these various Fc receptors, cell types expressing them,are not completely characterized. The above discussion merely reflectsthe current state-of-the-art regarding these receptors (see, e.g.,Immunobiology: The Immune System in Health & Disease, 5^(th) Edition,Janeway et al., Eds, 2001, ISBN 0-8153-3642-x, FIG. 9.30 at pp. 371),and is not intended to be limiting with respect to the myriad receptorsignaling cascades that can be regulated with the compounds describedherein.

“Fc Receptor-Mediated Degranulation” or “Fc Receptor-InducedDegranulation” refers to degranulation that proceeds via an Fc receptorsignal transduction cascade initiated by crosslinking of an Fc receptor.

“IgE-Induced Degranulation” or “FcεRI-Mediated Degranulation” refers todegranulation that proceeds via the IgE receptor signal transductioncascade initiated by crosslinking of FcεR1-bound IgE. The crosslinkingmay be induced by an IgE-specific allergen or other multivalent bindingagent, such as an anti-IgE antibody. Referring to FIG. 2, in mast and/orbasophil cells, the FcεRI signaling cascade leading to degranulation maybe broken into two stages: upstream and downstream. The upstream stageincludes all of the processes that occur prior to calcium ionmobilization (illustrated as “Ca^(2+”) in FIG. 2; see also FIG. 3). Thedownstream stage includes calcium ion mobilization and all processesdownstream thereof. Compounds that inhibit FcεRI-mediated degranulationmay act at any point along the FcεRI-mediated signal transductioncascade. Compounds that selectively inhibit upstream FcεRI-mediateddegranulation act to inhibit that portion of the FcεRI signaling cascadeupstream of the point at which calcium ion mobilization is induced. Incell-based assays, compounds that selectively inhibit upstreamFcεRI-mediated degranulation inhibit degranulation of cells such as mastor basophil cells that are activated or stimulated with an IgE-specificallergen or binding agent (such as an anti-IgE antibody) but do notappreciably inhibit degranulation of cells that are activated orstimulated with degranulating agents that bypass the FcεRI signalingpathway, such as, for example the calcium ionophores ionomycin andA23187.

“IgG-Induced Degranulation” or “FcγRI-Mediated Degranulation” refers todegranulation that proceeds via the FcγRI signal transduction cascadeinitiated by crosslinking of FcγRI-bound IgG. The crosslinking may beinduced by an IgG-specific allergen or another multivalent bindingagent, such as an anti-IgG or fragment antibody. Like the FcεRIsignaling cascade, in mast and basophil cells the FcγRI signalingcascade also leads to degranulation which may be broken into the sametwo stages: upstream and downstream. Similar to FcεRI-mediateddegranulation, compounds that selectively inhibit upstreamFcγRI-mediated degranulation act upstream of the point at which calciumion mobilization is induced. In cell-based assays, compounds thatselectively inhibit upstream FcγRI-mediated degranulation inhibitdegranulation of cells such as mast or basophil cells that are activatedor stimulated with an IgG-specific allergen or binding agent (such as ananti-IgG antibody or fragment) but do not appreciably inhibitdegranulation of cells that are activated or stimulated withdegranulating agents that bypass the FcγRI signaling pathway, such as,for example the calcium ionophores ionomycin and A23187.

“Ionophore-Induced Degranulation” or “Ionophore-Mediated Degranulation”refers to degranulation of a cell, such as a mast or basophil cell, thatoccurs upon exposure to a calcium ionophore such as, for example,ionomycin or A23187.

“Syk Kinsase” refers to the well-known 72 kDa non-receptor (cytoplasmic)spleen protein tyrosine kinase expressed in B-cells and otherhematopoetic cells. Syk kinase includes two consensus Src-homology 2(SH2) domains in tandem that bind to phosphorylated immunoreceptortyrosine-based activation motifs (“ITAMs”), a “linker” domain and acatalytic domain (for a review of the structure and function of Sykkinase see Sada et al., 2001, J. Biochem. (Tokyo) 130:177-186); see alsoTurner et al., 2000, Immunology Today 21:148-154). Syk kinase has beenextensively studied as an effector of B-cell receptor (BCR) signaling(Turner et al., 2000, supra). Syk kinase is also critical for tyrosinephosphorylation of multiple proteins which regulate important pathwaysleading from immunoreceptors, such as Ca²⁺ mobilization andmitogen-activated protein kinase (MAPK) cascades (see, e.g., FIG. 2) anddegranulation. Syk kinase also plays a critical role in integrinsignaling in neutrophils (see, e.g., Mocsai et al. 2002, Immunity16:547-558).

As used herein, Syk kinase includes kinases from any species of animal,including but not limited to, homosapiens, simian, bovine, porcine,rodent, etc., recognized as belonging to the Syk family. Specificallyincluded are isoforms, splice variants, allelic variants, mutants, bothnaturally occurring and man-made. The amino acid sequences of such Sykkinases are well known and available from GENBANK. Specific examples ofmRNAs encoding different isoforms of human Syk kinase can be found atGENBANK accession no. gi|21361552|ref|NM_003177.21,gi|496899|emb|Z29630. 1|HSSYKPTK[496899] andgi|15030258|gb|BC011399.1|BC011399[15030258], which are incorporatedherein by reference.

Skilled artisans will appreciate that tyrosine kinases belonging toother families may have active sites or binding pockets that are similarin three-dimensional structure to that of Syk. As a consequence of thisstructural similarity, such kinases, referred to herein as “Syk mimics,”are expected to catalyze phosphorylation of substrates phosphorylated bySyk. Thus, it will be appreciated that such Syk mimics, signaltransduction cascades in which such Syk mimics play a role andbiological responses effected by such Syk mimics and Syk mimic-dependentsignaling cascades may be regulated, and in particular inhibited, withthe 2,4-pyrimidinediamine compounds described herein.

“Syk-Dependent Signaling Cascade” refers to a signal transductioncascade in which Syk kinase plays a role. Non-limiting examples of suchSyk-dependent signaling cascades include the FcαRI, FcεRI, FcγRI,FcγRIII, BCR and integrin signaling cascades.

6.2 The 2,4-Pyrimidinediamine Compounds

The compounds of the invention are generally 2,4-pyrimidinediaminecompounds according to structural formula (I):

including salts, hydrates, solvates and N-oxides thereof, wherein:

L¹ and L² are each, independently of one another, selected from thegroup consisting of a direct bond and a linker;

R² is selected from the group consisting of (C1-C6) alkyl optionallysubstituted with one or more of the same or different R⁸ groups, (C3-C8)cycloalkyl optionally substituted with one or more of the same ordifferent R⁸ groups, cyclohexyl optionally substituted with one or moreof the same or different R⁸ groups, 3-8 membered cycloheteroalkyloptionally substituted with one or more of the same or different R⁸groups, (C5-C15) aryl optionally substituted with one or more of thesame or different R⁸ groups, phenyl optionally substituted with one ormore of the same or different R⁸ groups and 5-15 membered heteroaryloptionally substituted with one or more of the same or different R⁸groups;

R⁴ is selected from the group consisting of hydrogen, (C1-C6) alkyloptionally substituted with one or more of the same or different R⁸groups, (C3-C8) cycloalkyl optionally substituted with one or more ofthe same or different R⁸ groups, cyclohexyl optionally substituted withone or more of the same or different R⁸ groups, 3-8 memberedcycloheteroalkyl optionally substituted with one or more of the same ordifferent R⁸ groups, (C5-C15) aryl optionally substituted with one ormore of the same or different R⁸ groups, phenyl optionally substitutedwith one or more of the same or different R⁸ groups and 5-15 memberedheteroaryl optionally substituted with one or more of the same ordifferent R⁸ groups;

R⁵ is selected from the group consisting of R⁶, (C1-C6) alkyl optionallysubstituted with one or more of the same or different R⁸ groups, (C1-C4)alkanyl optionally substituted with one or more of the same or differentR⁸ groups, (C2-C4) alkenyl optionally substituted with one or more ofthe same or different R⁸ groups and (C2-C4) alkynyl optionallysubstituted with one or more of the same or different R⁸ groups;

each R⁶ is independently selected from the group consisting of hydrogen,an electronegative group, —OR^(d), —SR^(d), (C1-C3) haloalkyloxy,(C1-C3) perhaloalkyloxy, —NR^(c)R^(c), halogen, (C1-C3) haloalkyl,(C1-C3) perhaloalkyl, —CF₃, —CH₂CF₃, —CF₂CF₃, —CN, —NC, —OCN, —SCN, —NO,—NO₂, —N₃, —S(O)R^(d), —S(O)₂R^(d), —S(O)₂OR^(d), —S(O)NR^(c)R^(c),—S(O)₂NR^(c)R^(c), —OS(O)R^(d), —OS(O)₂R^(d), —OS(O)₂OR^(d),—OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d),—C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c), —OC(O)R^(d), —SC(O)R^(d),—OC(O)OR^(d), —SC(O)OR^(d), —OC(O)NR^(c)R^(c), —SC(O)NR^(c)R^(c),—OC(NH)NR^(c)R^(c), —SC(NH)NR^(c)R^(c), —[NHC(O)]_(n)R^(d),—[NHC(O)]_(n)OR^(d), —[NHC(O)]_(n)NR^(c)R^(c) and—[NHC(NH)]_(n)NR^(c)R^(c), (C5-C10) aryl optionally substituted with oneor more of the same or different R⁸ groups, phenyl optionallysubstituted with one or more of the same or different R⁸ groups,(C6-C16) arylalkyl optionally substituted with one or more of the sameor different R⁸ groups, 5-10 membered heteroaryl optionally substitutedwith one or more of the same or different R⁸ groups and 6-16 memberedheteroarylalkyl optionally substituted with one or more of the same ordifferent R⁸ groups;

R⁸ is selected from the group consisting of R^(a), R^(b), R^(a)substituted with one or more of the same or different R^(a) or R^(b),—OR^(a) substituted with one or more of the same or different R^(a) orR^(b), —B(OR^(a))₂, —B(NR^(c)R^(c))₂, —(CH₂)_(m)—R^(b),—(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—R^(b), —S—(CH₂)_(m)—R^(b),—O—CHR^(a)R^(b), —O—CR^(a)(R^(b))₂, —O—(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)—CH[(CH₂)_(m)R^(b)]R^(b), —S—(CHR^(a))_(m)—R^(b),—C(O)NH—(CH₂)_(m)—R^(b), —C(O)NH—(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),—S—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),—O—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b),—S—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b), —NH—(CH₂)_(m)—R^(b),—NH—(CHR^(a))_(m)—R^(b), —NH[(CH₂)_(m)R^(b)], —N[(CH₂)_(m)R^(b)]₂,—NH—C(O)—NH—(CH₂)_(m)—R^(b), —NH—C(O)—(CH₂)_(m)—CHR^(b)R^(b) and—NH—(CH₂)_(m)—C(O)—NH—(CH₂)_(m)—R^(b);

each R^(a) is independently selected from the group consisting ofhydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl,piperazinyl, homopiperazinyl, piperidinyl, 4-11 memberedcycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 memberedheteroarylalkyl;

each R^(b) is a suitable group independently selected from the groupconsisting of ═O, —OR^(d), (C1-C3) haloalkyloxy, —OCF₃, ═S, —SR^(d),═NR^(d), ═NOR^(d), —NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)R^(d), —S(O)₂R^(d), —S(O)₂OR^(d),—S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(d), —OS(O)₂R^(d),—OS(O)₂OR^(d), —OS(O)₂NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d),—C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c), —C(NR^(a))NR^(c)R^(c),—C(NOH)R^(a), —C(NOH)NR^(c)R^(c), —OC(O)R^(d), —OC(O)OR^(d),—OC(O)NR^(c)R^(c), —OC(NH)NR^(c)R^(c), —OC(NR^(a))NR^(c)R^(c),—[NHC(O)]R^(d), —[NR^(a)C(O)]_(n)R^(d), —[NHC(O)]_(n)OR^(d),—[NR^(a)C(O)]_(n)OR^(d), —[NHC(O)]_(n)NR^(c)R^(c),—[NR^(a)C(O)]_(n)NR^(c)R^(c), —[NHC(NH)]_(f)NR^(c)R^(c) and—[NR^(a)C(NR^(a))]_(n)NR^(c)R^(c);

each R^(c) is independently R^(a), or, alternatively, each R^(c) istaken together with the nitrogen atom to which it is bonded to form a 5to 8-membered cycloheteroalkyl or heteroaryl which may optionallyinclude one or more of the same or different additional heteroatoms andwhich is optionally substituted with one or more of the same ordifferent R^(a) or suitable R^(b) groups;

each R^(d) is independently R^(a);

each m is independently an integer from 1 to 3; and

each n is independently an integer from 0 to 3.

In the compounds of structural formula (I), L¹ and L² represent,independently of one another, a direct bond or a linker. Thus, as willbe appreciated by skilled artisans, the substituents R² and/or R⁴ may bebonded either directly to their respective nitrogen atoms or,alternatively, spaced away from their respective nitrogen atoms by wayof a linker. The identity of the linker is not critical and typicalsuitable linkers include, but are not limited to, (C1-C6) alkyldiyls,(C1-C6) alkanos and (C1-C6) heteroalkyldiyls, each of which may beoptionally substituted with one or more of the same or different R⁸groups, where R⁸ is as previously defined for structural formula (I). Ina specific embodiment, L¹ and L² are each, independently of one another,selected from the group consisting of a direct bond, (C1-C3) alkyldiyloptionally substituted with one or more of the same or different R^(a),suitable R^(b) or R⁹ groups and 1-3 membered heteroalkyldiyl optionallysubstituted with one or more of the same or different R^(a), suitableR^(b) or R⁹ groups, wherein R⁹ is selected from the group consisting of(C1-C3) alkyl, —OR^(a), —C(O)OR^(a), (C5-C10) aryl optionallysubstituted with one or more of the same or different halogens, phenyloptionally substituted with one or more of the same or differenthalogens, 5-10 membered heteroaryl optionally substituted with one ormore of the same or different halogens and 6 membered heteroaryloptionally substituted with one or more of the same or differenthalogens; and R^(a) and R^(b) are as previously defined for structuralformula (I). Specific R⁹ groups that may be used to substitute L¹ and L²include —OR^(a), —C(O)OR^(a), phenyl, halophenyl and 4-halophenyl,wherein R^(a) is as previously defined for structural formula (I).

In another specific embodiment, L¹ and L² are each, independently of oneanother, selected from the group consisting of methano, ethano andpropano, each of which may be optionally monosubstituted with an R⁹group, where R⁹ is as previously defined above.

In all of the above embodiments, specific R^(a) groups that may beincluded in R⁹ groups are selected from the group consisting ofhydrogen, (C1-C6) alkyl, phenyl and benzyl.

In still another specific embodiment, L¹ and L² are each a direct bondsuch that the 2,4-pyrimidinediamine compounds of the invention arecompounds according to structural formula (Ia):

including salts, hydrates, solvates and N-oxides thereof, wherein R²,R⁴, R⁵ and R⁶ are as previously defined for structural formula (I).Additional specific embodiments of the 2,4-pyrimidinediamine compoundsof the invention are described below.

In a first embodiment of the compounds of structural formulae (I) and(Ia), R², R⁴, R⁵, R⁶, L¹ and L² are as previously defined for theirrespective structures (I) and (Ia), with the proviso that R² is not3,4,5-trimethoxyphenyl, 3,4,5-tri (C1-C6) alkoxyphenyl or

where R²¹, R²² and R²³ are as defined for R¹, R² and R³, respectively ofU.S. Pat. No. 6,235,746, the disclosure of which is incorporated byreference. In a specific embodiment of this first embodiment, R²¹ ishydrogen, halo, straight-chain or branched (C1-C6) alkyl optionallysubstituted with one or more of the same or different R²⁵ groups,hydroxyl, (C1-C6) alkoxy optionally substituted with one or more of thesame or different phenyl or R²⁵ groups, thiol (—SH), (C1-C6) alkylthiooptionally substituted with one or more of the same or different phenylor R²⁵ groups, amino (—NH₂), —NHR²⁶ or —NR²⁶R²⁶; R²² and R²³ are each,independently of one another, a (C1-C6) straight-chain or branched alkyloptionally substituted with one or more of the same or different R²⁵groups; R²⁵ is selected from the group consisting of halo, hydroxyl,(C1-C6) alkoxy, thiol, (C1-C6) alkylthio, (C1-C6) alkylamino and (C1-C6)dialkylamino; and each R²⁶ is independently a (C1-C6) alkyl optionallysubstituted with one or more of the same or different phenyl or R²⁵groups or a —C(O)R²⁷, where R²⁷ is a (C1-C6) alkyl optionallysubstituted with one or more of the same or different phenyl or R²⁵groups.

In another specific embodiment of this first embodiment, R²¹ is methoxyoptionally substituted with one or more of the same or different halogroups and/or R²² and R²³ are each, independently of one another, amethyl or ethyl optionally substituted with one or more of the same ordifferent halo groups.

In a second embodiment of the compounds of structural formulae (I) and(Ia), R², R⁴, R⁵ and L² are as previously described for their respectivestructures (I) and (Ia), L¹ is a direct bond and R⁶ is hydrogen, withthe proviso that R² is not 3,4,5-trimethoxyphenyl, 3,4,5-tri (C1-C6)alkoxyphenyl or

where R²¹, R²² and R²³ are as defined above, in connection with thefirst embodiment.

In a third embodiment, the 2,4-pyrimidinediamine compounds of structuralformulae (I) and (Ia) exclude one or more of the following compounds:

N2,N4-bis(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R070790);

N2,N4-bis(2-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R081166);

N2,N4-bis(4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R088814);

N2,N4-bis(2-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine (R088815);

N2,N4-bisphenyl-5-fluoro-2,4-pyrimidinediamine (R091880);

N2,N4-bis(3-methylphenyl)-5-fluoro-2,4-pyrimidinediamine (R092788);

N2,N4-bis(3-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine (R067962);

N2,N4-bis(2,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine (R067963);

N2,N4-bis(3,4-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine (R067964);

N2,N4-bis(4-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine (R0707153);

N2,N4-bis(2,4-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine (R070791);

N2,N4-bis(3-bromophenyl)-5-fluoro-2,4-pyrimidinediamine (R008958);

N2,N4-bis(phenyl)-5-fluoro-2,4-pyrimidinediamine;

N2,N4-bis(morpholino)-5-fluoro-2,4-pyrimidinediamine; and

N2,N4-bis[(3-chloro-4-methoxyphenyl)]-5-fluoro-2,4-pyrimidinediamine.

In a fourth embodiment, the compounds of structural formulae (I) and(Ia) exclude compounds according to the following structural formula(Ib):

wherein R²⁴ is (C1-C6) alkyl; and R²¹, R²² and R²³ are as previouslydefined in connection with the first embodiment.

In a fifth embodiment, the compounds of structural formulae (I) and (Ia)exclude the compounds described in Examples 1-141 of U.S. Pat. No.6,235,746, the disclosure of which is incorporated herein by reference.

In a sixth embodiment, the compounds of structural formulae (I) and (Ia)exclude compounds defined by formula (1) or formula 1(a) of this U.S.Pat. No. 6,235,746 (see, e.g., the disclosure at Col. 1, line 48 throughCol. 7, line 49 and Col. 8, lines 9-36, which is incorporated byreference).

In a seventh embodiment, the compounds of structural formulae (I) and(Ia) exclude compounds in which R⁵ is cyano or —C(O)NHR, where R ishydrogen or (C1-C6) alkyl, when R² is a substituted phenyl; R4 is asubstituted or unsubstituted (C1-C6) alkyl, (C₃-C₅) cycloalkyl, 3-8membered cycloheteralkyl or 5-15 membered heteroaryl; and R⁶ ishydrogen.

In an eighth embodiment, the compounds of structural formulae (I) and(Ia) exclude the compounds defined by formulae (I) and (X) of WO02/04429 or any compound disclosed in WO 02/04429, the disclosure ofwhich is incorporated herein by reference.

In a ninth embodiment of the compounds of structural formulae (I) and(Ia), when R⁵ is cyano or —C(O)NHR, where R is hydrogen or (C1-C6)alkyl; and R⁶ is hydrogen, then R² is other than a substituted phenylgroup.

In a tenth embodiment, the compounds of structural formulae (I) and (Ia)exclude compounds in which R² and R⁴ are each independently asubstituted or unsubstituted pyrrole or indole ring which is attached tothe remainder of the molecule via its ring nitrogen atom.

In an eleventh embodiment, the compounds of structural formulae (I) and(Ia) exclude compounds defined by formulae (I) and (IV) of U.S. Pat. No.4,983,608 or any compound disclosed in U.S. Pat. No. 4,983,608, thedisclosure of which is incorporated herein by reference.

Those of skill in the art will appreciate that in the compounds offormulae (I) and (Ia), R² and R⁴ may be the same or different, and mayvary broadly. When R² and/or R⁴ are optionally substituted rings, suchas optionally substituted cycloalkyls, cycloheteroalkyls, aryls andheteroaryls, the ring may be attached to the remainder of the moleculethrough any available carbon or heteroatom. The optional substituentsmay be attached to any available carbon atoms and/or heteroatoms.

In a twelfth embodiment of the compounds of structural formulae (I) and(Ia), R² and/or R⁴ is an optionally substituted phenyl or an optionallysubstituted (C5-C15) aryl, subject to the provisos that (1) when R⁶ ishydrogen, then R² is not 3,4,5-trimethoxyphenyl or 3,4,5-tri (C1-C6)alkoxyphenyl; (2) when R² is a 3,4,5-trisubstituted phenyl, then thesubstituents at the 3- and 4-positions are not simultaneously methoxy or(C1-C6) alkoxy; or (3) when R⁶ is hydrogen and R⁴ is (C1-C6) alkyl,(C₃-C₈) cycloalkyl, 3-8 membered cycloheteroalkyl or 5-15 memberedheteroaryl, then R⁵ is other than cyano. Alternatively, R² is subject tothe provisos described in connection with the first or secondembodiments. The optionally substituted aryl or phenyl group may beattached to the remainder of the molecule through any available carbonatom. Specific examples of optionally substituted phenyls includephenyls that are optionally mono-, di- or tri-substituted with the sameor different R⁸ groups, where R⁸ is as previously defined for structuralformula (I) and subject to the above provisos. When the phenyl ismono-substituted, the R⁸ substituent may be positioned at either theortho, meta orpara position. When positioned at the ortho, meta orparaposition, R⁸ is preferably selected from the group consisting of(C1-C10) alkyl, (C1-C10) branched alkyl, —OR^(a) optionally substitutedwith one or more of the same or different R^(b) groups, —O—C(O)OR^(a),—O—(CH₂)_(m)—C(O)OR^(a), —C(O)OR^(a), —O—(CH₂)_(m)—NR^(c)R^(c),—O—C(O)NR^(c)R^(c), —O—(CH₂)_(m)—C(O)NR^(c)R^(c), —O—C(NH)NR^(c)R^(c),—O—(CH₂)_(m)—C(NH)NR^(c)R^(c) and —NH—(CH₂)_(m)—NR^(c)R^(c), where m,R^(a) and R^(c) are as previously defined for structural formula (I). Inone embodiment of these compounds, —NR^(c)R^(c) is a 5-6 memberedheteroaryl which optionally includes one or more of the same ordifferent additional heteroatoms. Specific examples of such 5-6 memberedheteroaryls include, but are not limited to, oxadiazolyl, triazolyl,thiazolyl, oxazolyl, tetrazolyl and isoxazolyl.

In another embodiment of these compounds, —NR^(c)R^(c) is a 5-6 memberedsaturated cycloheteroalkyl ring which optionally includes one or more ofthe same or different heteroatoms. Specific examples of suchcycloheteroalkyls include, but are not limited to, pyrrolidinyl,pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl.In still another embodiment of these compounds, each R^(a) isindependently a (C1-C6) alkyl and/or each —NR^(c)R^(c) is —NHR^(a),where R^(a) is a (C1-C6) alkyl. In one specific embodiment, R⁸ is—O—CH₂—C(O)NHCH₃. In another specific embodiment R⁸ is —OH.

When the phenyl is di-substituted or tri-substituted, the R⁸substituents may be positioned at any combination of positions. Forexample, the R⁸ substituents may be positioned at the 2,3-, 2,4-, 2,5-,2,6-, 3,4-, 3,5-, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6-, 2,5,6- or3,4,5-positions. In one embodiment of compounds including adisubstituted phenyl, the substituents are positioned other than 3,4. Inanother embodiment they are positioned 3,4. In one embodiment ofcompounds including a trisubstituted phenyl, the substituents arepositioned other than 3,4,5 or, alternatively, no two of thesubstituents are positioned 3,4. In another embodiment, the substituentsare positioned 3,4,5.

Specific examples of R⁸ substituents in such di- and trisubstitutedphenyls include the various R⁸ substituents described above inconnection with the ortho, meta and para substituted phenyls.

In another specific embodiment, R⁸ substituents useful for substitutingsuch di- and trisubstituted phenyls include (C1-C6) alkyl, (C1-C6)alkoxy, methoxy, halo, chloro, (C1-C6) perhaloalkyl, —CF₃, (C1-C6)perhaloalkoxy and —OCF₃. In a preferred embodiment, such R⁸ substituentsare positioned 3,4 or 3,5. Specific examples of preferred di-substitutedphenyl rings include 3-chloro-4-methoxy-phenyl,3-methoxy-4-chlorophenyl, 3-chloro-4-trifluoromethoxy-phenyl,3-trifluoromethoxy-4-chloro-phenyl, 3,4-dichloro-phenyl,3,4-dimethoxyphenyl and 3,5-dimethoxyphenyl, with the provisos that: (1)when R⁴ is one of the above-identified phenyls, and R⁵ and R⁶ are eachhydrogen, then R² is not 3,4,5-tri(C1-C6)alkoxyphenyl or3,4,5-trimethoxyphenyl; (2) when R² is 3,4-dimethoxyphenyl and R⁵ and R⁶are each hydrogen, then R4 is not 3-(C1-C6)alkoxyphenyl,3-methoxyphenyl, 3,4-di-(C1-C6) alkoxyphenyl or 3,4-dimethoxyphenyl; (3)when R⁴ is 3-chloro-4-methoxyphenyl and R⁵ is halo or fluoro, andoptionally R⁶ is hydrogen, then R² is not 3-chloro-4-(C1-C6)alkoxyphenylor 3-chloro-4-methoxyphenyl; (4) when R⁴ is 3,4-dichlorophenyl, R⁵ ishydrogen, (C1-C6) alkyl, methyl, halo or chloro and optionally R⁶ ishydrogen, then R² is not a phenyl mono substituted at the para positionwith a (C1-C6) alkoxy group which is optionally substituted with one ormore of the same or different R^(b), —OH or —NR^(c)R^(c) groups, whereR^(b) and R^(c) are as previously described for structural formula (I);and/or (5) R² and/or R⁴ is not 3,4,5-tri(C1-C6)alkoxyphenyl or3,4,5-trimethoxyphenyl, especially when R⁵ and R⁶ are each hydrogen.

In another embodiment of compounds including a trisubstituted phenyl,the trisubstituted phenyl has the formula:

wherein: R³¹ is methyl or (C1-C6) alkyl; R³² is hydrogen, methyl or(C1-C6) alkyl; and R³³ is a halo group.

In a thirteenth embodiment of the compounds of structural formulae (I)and (Ia), R² and/or R⁴ is an optionally substituted heteroaryl. Typicalheteroaryl groups according to this thirteenth embodiment comprise from5 to 15, and more typically from 5 to 11 ring atoms, and include one,two, three or four of the same or different heteratoms or heteroatomicgroups selected from the group consisting of N, NH, O, S, S(O) andS(O)₂. The optionally substituted heteroaryl may be attached to itsrespective C2 or C4 nitrogen atom or linker L¹ or L² through anyavailable carbon atom or heteroatom, but is typically attached via acarbon atom. The optional substituents may be the same or different, andmay be attached to any available carbon atom or heteroatom. In oneembodiment of these compounds, R⁵ is other than bromo, nitro,trifluoromethyl, cyano or —C(O)NHR, where R is hydrogen or (C1-C6)alkyl. In another embodiment of these compounds, when R² and R⁴ are eacha substituted or unsubstituted pyrrole or indole, then the ring isattached to the remainder of the molecule via a ring carbon atom. Instill another embodiment of compounds including an optionallysubstituted heteroaryl group, the heteroaryl is unsubstituted orsubstituted with from one to four of the same or different R⁸ groups,where R⁸ is as previously defined for structural formula (I). Specificexamples of such optionally substituted heteroaryls include, but are notlimited to, the following heteroaryl groups:

wherein:

-   -   p is an integer from one to three;    -   each        independently represents a single bond or a double bond;    -   R³⁵ is hydrogen or R⁸, where R⁸ is as previously defined for        structural formula (I);    -   X is selected from the group consisting of CH, N and N—O;    -   each Y¹ is independently selected from the group consisting of        O, S, SO, SO, SONR³⁶, NH and NR³⁷;    -   each Y² is independently selected from the group consisting of        CH, CH₂, O, S, N, NH and NR³⁷;    -   R³⁶ is hydrogen or alkyl;    -   R³⁷ is selected from the group consisting of hydrogen and a        progroup, preferably hydrogen or a progroup selected from the        group consisting of aryl, arylalkyl, heteroaryl, R^(a),        R^(b)—CR^(a)R^(b)—O—C(O)R⁸, —CR^(a)R^(b)—O—PO(OR⁸)₂,        —CH₂—O—PO(OR⁸)₂, —CH₂—PO(OR⁸)₂, —C(O)—CR^(a)R^(b)—N(CH₃)₂,        —CR^(a)R^(b)—O—C(O)—CR^(a)R^(b)—N(CH₃)₂, —C(O)R⁸, —C(O)CF₃ and        —C(O)—NR⁸—C(O)R⁸;    -   A is selected from the group consisting of O, NH and NR³⁸;    -   R³⁸ is selected from the group consisting of alkyl and aryl;    -   R⁹, R¹⁰, R″ and R¹² are each, independently of one another,        selected from the group consisting of alkyl, alkoxy, halogen,        haloalkoxy, aminoalkyl and hydroxyalkyl, or, alternatively, R⁹        and R¹⁰ and/or R¹¹ and R¹² are taken together form a ketal;    -   each Z is selected from the group consisting of hydroxyl,        alkoxy, aryloxy, ester, carbamate and sulfonyl;    -   Q is selected from the group consisting of —OH, OR⁸,        —NR^(c)R^(c), —NHR³⁹—C(O)R⁸, —NHR³⁹—C(O)OR⁸, —NR³⁹—CHR⁴⁰—R^(b),        —NR³⁹—(CH₂)_(m)—R^(b) and —NR³⁹—C(O)—CHR⁴⁰—NR^(c)R^(c);

R³⁹ and R⁴⁰ are each, independently of one another, selected from thegroup consisting of hydrogen, alkyl, aryl, alkylaryl, arylalkyl andNHR⁸; and

R^(a), R^(b) and R^(c) are as previously defined for structural formula(I). Preferred R^(b) substitutents for Q are selected from —C(O)OR⁸,—O—C(O)R⁸, —O—P(O)(OR⁸)₂ and —P(O)(OR⁸)₂.

In one embodiment of the above-depicted heteroaryls, as well as other5-15 membered heteroaryls according to this embodiment of the invention,each R⁸ is independently selected from the group consisting of R^(d),—NR^(c)R^(c), —(CH₂)_(m)—NR^(c)R^(c), —C(O)NR^(c)R^(c),—(CH₂)_(m)—C(O)NR^(c)R^(c), —C(O)OR^(d), —(CH₂)_(m)—C(O)OR^(d) and—(CH₂)_(m)—OR^(d), where m, R^(c) and R^(d) are as previously definedfor structural formula (I).

In a specific embodiment, R^(d) and/or R^(c) is selected from the groupconsisting of R^(a) and (C3-C8) cycloalkyl optionally substituted withone or more of the same or different hydroxyl, amino or carboxyl groups.

In another embodiment of the above-depicted heteroaryls, each R³⁵ ishydrogen or (C1-C6) ethyl or methyl.

In still another embodiment of the above-depicted heteroaryls, thearomatic ring connectivity is either at the 5 or 6 position. It shouldbe understood that either R² or R⁴ can utilize the heteroaryl groupsdiscussed throughout this specification.

In a fourteenth embodiment of the compounds of structural formulae (I)and (Ia), R² and R⁴ are each, independently of one another, anoptionally substituted phenyl, aryl or heteroaryl, with the provisosthat: (1) when L¹ is a direct bond and R⁶ and optionally R⁵ is hydrogen,then R² is other than 3,4,5-trimethoxyphenyl or 3,4,5-tri(C1-C6)alkoxyphenyl; (2) when L¹ and L² are each a direct bond, R⁶ is hydrogenand R⁵ is halo, then R² and R⁴ are not each simultaneously3,4,5-trimethoxyphenyl or 3,4,5-tri(C1-C6) alkoxyphenyl; (3) when R⁴ is3-methoxyphenyl or 3-(C1-C6) alkoxyphenyl and R² is a3,4,5-trisubstituted phenyl, the substituents positioned at the 3 and 4positions are not both simultaneously methoxy or (C1-C6) alkoxy; (4)when R² is a substituted phenyl and R⁶ is hydrogen, then R⁵ is otherthan cyano or —C(O)NHR, where R is hydrogen or (C1-C6) alkyl; and/or (5)when R² and R⁴ are each independently a substituted or unsubstitutedpyrrole or indole, then the pyrrole or indole is attached to theremainder of the molecule via a ring carbon atom. Alternatively, R² issubject to the provisos described in connection with the first or secondembodiment.

In this fourteenth embodiment of the invention, the R² and R⁴substituents may be the same or different. Specific optionallysubstituted phenyl, aryl and/or heteroaryls include those illustratedabove in connection with the twelfth and thirteenth embodiments.

In a fifteenth embodiment of the compounds of structural formulae (I)and (Ia), including the above-described first through fourteenthembodiments thereof, R⁶ is hydrogen and R⁵ is an electronegative group.As will be recognized by skilled artisans, electronegative groups areatoms or groups of atoms that have a relatively great tendency toattract electrons to themselves. Specific examples of electronegativegroups according to this fourteenth embodiment include, but are notlimited to, —CN, —NC, —NO₂, halo, bromo, chloro, fluoro, (C1-C3)haloalkyl, (C1-C3) perhaloalkyl, (C1-C3) fluoroalkyl, (C1-C3)perfluoroalkyl, —CF₃, (C1-C3) haloalkoxy, (C1-C3) perhaloalkoxy, (C1-C3)fluoroalkoxy, (C1-C3) perfluoroalkoxy, —OCF₃, —C(O)R^(a), —C(O)OR^(a),—C(O)CF₃ and —C(O)OCF₃. In a specific embodiment, the electronegativegroup is a halogen-containing electronegative group, such as —OCF₃,—CF₃, bromo, chloro or fluoro. In another specific embodiment, R⁵ isfluoro, subject to the proviso that the compound is not any compoundaccording to the third embodiment.

In a sixteenth embodiment, the compounds of structural formulae (I) and(Ia) are compounds according to structural formula (Ib):

and salts, hydrates, solvates and N-oxides thereof, wherein R¹¹, R¹²,R¹³ and R¹⁴ are each, independently of one another, selected from thegroup consisting of hydrogen, hydroxy, (C1-C6) alkoxy and —NR^(c)R^(c);and R⁵, R⁶ and R^(c) are as previously defined for structural formula(I), with the proviso that when R¹³, R⁵ and R⁶ are each hydrogen, thenR¹¹ and R¹² are not simultaneously methoxy, (C1-C6) alkoxy or (C1-C6)haloalkoxy

In a seventeenth embodiment, the compounds of structural formulae (I)and (Ia) are compounds according to structural formula (Ic):

and salts, hydrates, solvates and N-oxides thereof, wherein:

R⁴ is selected from the group consisting of 5-10 membered heteroaryl and3-hydroxyphenyl;

R⁵ is F or —CF₃; and

R⁸ is —O(CH₂)_(m)—R^(b), where m and R^(b) are as previously defined forstructural formula (I).

In a specific embodiment, R⁸ is —O—CH₂—C(O)NH—CH₃ and/or R⁴ is aheteroaryl according to the thirteenth embodiment.

In an eighteenth embodiment, the compounds of structural formulae (I)and (Ia) include any compound selected from TABLE 1 that inhibits an Fcreceptor signal transduction cascade, a Syk kinase activity, aSyk-kinase dependent receptor signal transduction cascade orcelldegranulation as measured in an in vitro assay, optionally subject tothe proviso that the compound is not a compound excluded by theabove-described third embodiment and/or other embodiments. In a specificembodiment, such compounds have an IC₅₀ of about 20 μM or less asmeasured in an in vitro degranulation assay, such as one of thedegranulation assays described in the Examples section.

In a nineteenth embodiment, the compounds of structural formulae (I) and(Ia) include any compound selected from TABLE 1 that inhibits the FcγR1or FcεR1 receptor cascade with an IC₅₀ of about 20 μM or less asmeasured in an in vitro assay, such as one of the in vitro assaysprovided in the Examples section, optionally subject to the proviso thatthe compound is not a compound excluded by the above-described thirdembodiment and/or other embodiments.

Also specifically described are combinations of the above first throughnineteenth specific embodiments.

Those of skill in the art will appreciate that the 2,4-pyrimidinediaminecompounds described herein may include functional groups that can bemasked with progroups to create prodrugs. Such prodrugs are usually, butneed not be, pharmacologically inactive until converted into theiractive drug form. Indeed, many of the active 2,4-pyrimidinediaminecompounds described in TABLE 1, infra, include promoieties that arehydrolyzable or otherwise cleavable under conditions of use. Forexample, ester groups commonly undergo acid-catalyzed hydrolysis toyield the parent carboxylic acid when exposed to the acidic conditionsof the stomach, or base-catalyzed hydrolysis when exposed to the basicconditions of the intestine or blood. Thus, when administered to asubject orally, 2,4-pyrimidinediamines that include ester moieties maybe considered prodrugs of their corresponding carboxylic acid,regardless of whether the ester form is pharmacologically active.Referring to TABLE 1, numerous ester-containing 2,4-pyrimidinediaminesof the invention are active in their ester, “prodrug” form.

In the prodrugs of the invention, any available functional moiety may bemasked with a progroup to yield a prodrug. Functional groups within the2,4-pyrimidinediamine compounds that may be masked with progroups forinclusion in a promoiety include, but are not limited to, amines(primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, etc.Myriad progroups suitable for masking such functional groups to yieldpromoieties that are cleavable under the desired conditions of use areknown in the art. All of these progroups, alone or in combinations, maybe included in the prodrugs of the invention.

In one illustrative embodiment, the prodrugs of the invention arecompounds according to structural formula (I) in which R^(c) and R^(d)may be, in addition to their previously-defined alternatives, aprogroup.

Replacing the hydrogens attached to N2 and N4 in the2,4-pyrimidinediamines of structural formula (I) with substituentsadversely effects the activity of the compounds. However, as will beappreciated by skilled artisans, these nitrogens may be included inpromoieties that, under conditions of use, cleave to yield2,4-pyrimidinediamines according to structural formula (I). Thus, inanother embodiment, the prodrugs of the invention are compoundsaccording to structural formula (II):

including salts, hydrates, solvates and N-oxides thereof, wherein: R²,R⁴, R⁵, R⁶, L¹ and L² are as previously defined for structural formula(I); and R^(2b) and R^(4b) are each, independently of one another, aprogroup. Specific examples of progroups according to this embodiment ofthe invention include, but are not limited to, (C1-C6) alkyl, —C(O)CH₃,—C(O)NHR³⁶ and —S(O)₂R³⁶, where R³⁶ is (C1-C6) alkyl, (C5-C15) aryl and(C3-C8) cycloalkyl.

In the prodrugs of structural formula (II), the various substituents maybe as described for the various first through twentieth embodimentspreviously described for the compounds of structural formulae (I) and(Ia), or combinations of such embodiments.

Those of skill in the art will appreciate that many of the compounds andprodrugs of the invention, as well as the various compound speciesspecifically described and/or illustrated herein, may exhibit thephenomena of tautomerism, conformational isomerism, geometric isomerismand/or optical isomerism. For example, the compounds and prodrugs of theinvention may include one or more chiral centers and/or double bonds andas a consequence may exist as stereoisomers, such as double-bond isomers(i.e., geometric isomers), enantiomers and diasteromers and mixturesthereof, such as racemic mixtures. As another example, the compounds andprodrugs of the invention may exist in several tautomeric forms,including the enol form, the keto form and mixtures thereof. As thevarious compound names, formulae and compound drawings within thespecification and claims can represent only one of the possibletautomeric, conformational isomeric, optical isomeric or geometricisomeric forms, it should be understood that the invention encompassesany tautomeric, conformational isomeric, optical isomeric and/orgeometric isomeric forms of the compounds or prodrugs having one or moreof the utilities described herein, as well as mixtures of these variousdifferent isomeric forms. In cases of limited rotation around the2,4-pryimidinediamine core structure, atrop isomers are also possibleand are also specifically included in the compounds of the invention.

Moreover, skilled artisans will appreciate that when lists ofalternative substituents include members which, owing to valencyrequirements or other reasons, cannot be used to substitute a particulargroup, the list is intended to be read in context to include thosemembers of the list that are suitable for substituting the particulargroup. For example, skilled artisans will appreciate that while all ofthe listed alternatives for R^(b) can be used to substitute an alkylgroup, certain of the alternatives, such as ═O, cannot be used tosubstitute a phenyl group. It is to be understood that only possiblecombinations of substituent-group pairs are intended.

The compounds and/or prodrugs of the invention may be identified byeither their chemical structure or their chemical name. When thechemical structure and the chemical name conflict, the chemicalstructure is determinative of the identity of the specific compound.

Depending upon the nature of the various substituents, the2,4-pyrimidinediamine compounds and prodrugs of the invention may be inthe form of salts. Such salts include salts suitable for pharmaceuticaluses (“pharmaceutically-acceptable salts”), salts suitable forveterinary uses, etc. Such salts may be derived from acids or bases, asis well-known in the art.

In one embodiment, the salt is a pharmaceutically acceptable salt.Generally, pharmaceutically acceptable salts are those salts that retainsubstantially one or more of the desired pharmacological activities ofthe parent compound and which are suitable for administration to humans.Pharmaceutically acceptable salts include acid addition salts formedwith inorganic acids or organic acids. Inorganic acids suitable forforming pharmaceutically acceptable acid addition salts include, by wayof example and not limitation, hydrohalide acids (e.g., hydrochloricacid, hydrobromic acid, hydriodic, etc.), sulfuric acid, nitric acid,phosphoric acid, and the like. Organic acids suitable for formingpharmaceutically acceptable acid addition salts include, by way ofexample and not limitation, acetic acid, trifluoroacetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalicacid, pyruvic acid, lactic acid, malonic acid, succinic acid, malicacid, maleic acid, fumaric acid, tartaric acid, citric acid, palmiticacid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid,mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid,ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonicacid, etc.), arylsulfonic acids (e.g., benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, etc.),4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like.

Pharmaceutically acceptable salts also include salts formed when anacidic proton present in the parent compound is either replaced by ametal ion (e.g., an alkali metal ion, an alkaline earth metal ion or analuminum ion) or coordinates with an organic base (e.g., ethanolamine,diethanolamine, triethanolamine, N-methylglucamine, morpholine,piperidine, dimethylamine, diethylamine, etc.).

The 2,4-pyrimidinediamine compounds and of the invention, as well as thesalts thereof, may also be in the form of hydrates, solvates andN-oxides, as are well-known in the art.

6.3 Methods of Synthesis

The compounds and prodrugs of the invention may be synthesized via avariety of different synthetic routes using commercially availablestarting materials and/or starting materials prepared by conventionalsynthetic methods. Suitable exemplary methods that may be routinelyadapted to synthesize the 2,4-pyrimidinediamine compounds and prodrugsof the invention are found in U.S. Pat. No. 5,958,935, the disclosure ofwhich is incorporated herein by reference. Specific examples describingthe synthesis of numerous compounds and prodrugs of the invention, aswell as intermediates therefor, are provided in the Examples section.All of the compounds of structural formulae (I), (Ia) and (II) may beprepared by routine adaptation of these methods.

A variety of exemplary synthetic routes that can be used to synthesizethe 2,4-pyrimidinediamine compounds of the invention are described inSchemes (I)-(XI), below. In Schemes (I)-(XI), like-numbered compoundshave similar structures. These methods may be routinely adapted tosynthesize the prodrugs according to structural formula (II).

In one exemplary embodiment, the compounds can be synthesized fromsubstituted or unsubstituted uracils or thiouracils as illustrated inScheme (I), below:

In Scheme (I), R², R⁴, R⁵, R⁶, L¹ and L² are as previously defined forstructural formula (I), X is a halogen (e.g., F, Cl, Br or I) and Y andY′ are each, independently of one another, selected from the groupconsisting of O and S. Referring to Scheme (I), uracil or thiouracil 2is dihalogenated at the 2- and 4-positions using standard halogenatingagent POX₃ (or other standard halogenating agent) under standardconditions to yield 2,4-bishalo pyrimidine 4. Depending upon the R⁵substituent, in pyrimidine 4, the halide at the C4 position is morereactive towards nucleophiles than the halide at the C2 position. Thisdifferential reactivity can be exploited to synthesize2,4-pyrimidinediamines according structural formula (I) by firstreacting 2,4-bishalopyrimidine 4 with one equivalent of amine 10,yielding 4N-substituted-2-halo-4-pyrimidineamine 8, followed by amine 6to yield a 2,4-pyrimidinediamine according structural formula (I).2N,4N-bis(substituted)-2,4-pyrimidinediamines 12 and 14 can be obtainedby reacting 2,4-bishalopyrimidine 4 with excess 6 or 10, respectively.

In most situations, the C4 halide is more reactive towards nucleophiles,as illustrated in the Scheme. However, as will be recognized by skilledartisans, the identity of the R⁵ substituent may alter this reactivity.For example, when R⁵ is trifluoromethyl, a 50:50 mixture of4N-substituted-4-pyrimidineamine 8 and the corresponding2N-substituted-2-pyrimidineamine is obtained. Regardless of the identityof the R⁵ substituent, the regioselectivity of the reaction can becontrolled by adjusting the solvent and other synthetic conditions (suchas temperature), as is well-known in the art.

The reactions depicted in Scheme (I) may proceed more quickly when thereaction mixtures are heated via microwave. When heating in thisfashion, the following conditions may be used: heat to 175° C. inethanol for 5-20 min. in a Smith Reactor (Personal Chemistry) in asealed tube (at 20 bar pressure).

The uracil or thiouracil 2 starting materials may be purchased fromcommercial sources or prepared using standard techniques of organicchemistry. Commercially available uracils and thiouracils that can beused as starting materials in Scheme (I) include, by way of example andnot limitation, uracil (Aldrich #13,078-8; CAS Registry 66-22-8);2-thio-uracil (Aldrich #11,558-4; CAS Registry 141-90-2);2,4-dithiouracil (Aldrich #15,846-1; CAS Registry 2001-93-6);5-acetouracil (Chem. Sources Int'l 2000; CAS Registry 6214-65-9);5-azidouracil; 5-aminouracil (Aldrich #85,528-6; CAS Registry 932-52-5);5-bromouracil (Aldrich #85,247-3; CAS Registry 51-20-7);5-(trans-2-bromovinyl)-uracil (Aldrich #45,744-2; CAS Registry69304-49-0); 5-(trans-2-chlorovinyl)-uracil (CAS Registry 81751-48-2);5-(trans-2-carboxyvinyl)-uracil; uracil-5-carboxylic acid(2,4-dihydroxypyrimidine-5-carboxylic acid hydrate; Aldrich #27,770-3;CAS Registry 23945-44-0); 5-chlorouracil (Aldrich #22,458-8; CASRegistry 1820-81-1); 5-cyanouracil (Chem. Sources Int'l 2000; CASRegistry 4425-56-3); 5-ethyluracil (Aldrich #23,044-8; CAS Registry4212-49-1); 5-ethenyluracil (CAS Registry 37107-81-6); 5-fluorouracil(Aldrich #85,847-1; CAS Registry 51-21-8); 5-iodouracil (Aldrich#85,785-8; CAS Registry 696-07-1); 5-methyluracil (thymine; Aldrich#13,199-7; CAS Registry 65-71-4); 5-nitrouracil (Aldrich #85,276-7; CASRegistry 611-08-5); uracil-5-sulfamic acid (Chem. Sources Int'l 2000;CAS Registry 5435-16-5); 5-(trifluoromethyl)-uracil (Aldrich #22,327-1;CAS Registry 54-20-6); 5-(2,2,2-trifluoroethyl)-uracil (CAS Registry155143-31-6); 5-(pentafluoroethyl)-uracil (CAS Registry 60007-38-3);6-aminouracil (Aldrich #A5060-6; CAS Registry 873-83-6)uracil-6-carboxylic acid (orotic acid; Aldrich #0-840-2; CAS Registry50887-69-9); 6-methyluracil (Aldrich #D11,520-7; CAS Registry 626-48-2);uracil-5-amino-6-carboxylic acid (5-aminoorotic acid; Aldrich #19,121-3;CAS Registry #7164-43-4); 6-amino-5-nitrosouracil(6-amino-2,4-dihydroxy-5-nitrosopyrimidine; Aldrich #27,689-8; CASRegistry 5442-24-0); uracil-5-fluoro-6-carboxylic acid (5-fluorooroticacid; Aldrich #42,513-3; CAS Registry 00000-00-0); anduracil-5-nitro-6-carboxylic acid (5-nitroorotic acid; Aldrich #18,528-0;CAS Registry 600779-49-9). Additional 5-, 6- and 5,6-substituted uracilsand/or thiouracils are available from General Intermediates of Canada,Inc., Edmonton, CA (www.generalintermediates.com) and/or Interchim,Cedex, France (www.interchim.com), or may be prepared using standardtechniques. Myriad textbook references teaching suitable syntheticmethods are provided infra.

Amines 6 and 10 may be purchased from commercial sources or,alternatively, may be synthesized utilizing standard techniques. Forexample, suitable amines may be synthesized from nitro precursors usingstandard chemistry. Specific exemplary reactions are provided in theExamples section. See also Vogel, 1989, Practical Organic Chemistry,Addison Wesley Longman, Ltd. and John Wiley & Sons, Inc.

Skilled artisans will recognize that in some instances, amines 6 and 10and/or substituents R⁵ and/or R⁶ on uracil or thiouracil 2 may includefunctional groups that require protection during synthesis. The exactidentity of any protecting group(s) used will depend upon the identityof the functional group being protected, and will be apparent to theseof skill in the art. Guidance for selecting appropriate protectinggroups, as well as synthetic strategies for their attachment andremoval, may be found, for example, in Greene & Wuts, Protective Groupsin Organic Synthesis, 3d Edition, John Wiley & Sons, Inc., New York(1999) and the references cited therein (hereinafter “Greene & Wuts”).

A specific embodiment of Scheme (I) utilizing 5-fluorouracil (Aldrich#32,937-1) as a starting material is illustrated in Scheme (Ia), below:

In Scheme (Ia), R², R⁴, L¹ and L² are as previously defined for Scheme(I). According to Scheme (Ia), 5-fluorouracil 3 is halogenated withPOCl₃ to yield 2,4-dichloro-5-fluoropyrimidine 5, which is then reactedwith excess amine 6 or 10 to yield N2,N4-bis substituted5-fluoro-2,4-pyrimidinediamine 11 or 13, respectively. Alternatively,asymmetric 2N,4N-disubstituted-5-fluoro-2,4-pyrimidinediamine 9 may beobtained by reacting 2,4-dichloro-5-fluoropyrimidine 5 with oneequivalent of amine 10 (to yield2-chloro-N4-substituted-5-fluoro-4-pyrimidineamine 7) followed by one ormore equivalents of amine 6.

In another exemplary embodiment, the 2,4-pyrimidinediamine compounds ofthe invention may be synthesized from substituted or unsubstitutedcytosines as illustrated in Schemes (IIa) and (IIb), below:

In Schemes (IIa) and (IIb), R², R⁴, R⁵, R⁶, L¹, L² and X are aspreviously defined for Scheme (I) and PG represents a protecting group.Referring to Scheme (IIa), the C4 exocyclic amine of cytosine 20 isfirst protected with a suitable protecting group PG to yieldN4-protected cytosine 22. For specific guidance regarding protectinggroups useful in this context, see Vorbruggen and Ruh-Pohlenz, 2001,Handbook of Nucleoside Synthesis, John Wiley & Sons, NY, pp. 1-631(“Vorbruiggen”). Protected cytosine 22 is halogenated at the C2 positionusing a standard halogenation reagent under standard conditions to yield2-chloro-4N-protected-4-pyrimidineamine 24. Reaction with amine 6followed by deprotection of the C4 exocyclic amine and reaction withamine 10 yields a 2,4-pyrimidinediamine according to structural formula(I).

Alternatively, referring to Scheme (IIb), cytosine 20 may be reactedwith amine 10 or protected amine 21 to yield N4-substituted cytosine 23or 27, respectively. These substituted cytosines may then be halogenatedas previously described, deprotected (in the case of N4-substitutedcytosine 27) and reacted with amine 6 to yield a 2,4-pyrimidinediamineaccording to structural formula (I).

Commercially-available cytosines that may be used as starting materialsin Schemes (IIa) and (IIb) include, but are not limited to, cytosine(Aldrich #14,201-8; CAS Registry 71-30-7); N⁴-acetylcytosine (Aldrich#37,791-0; CAS Registry 14631-20-0); 5-fluorocytosine (Aldrich#27,159-4; CAS Registry 2022-85-7); and 5-(trifluoromethyl)-cytosine.Other suitable cytosines useful as starting materials in Schemes (IIa)are available from General Intermediates of Canada, Inc., Edmonton, CA(www.generalintermediates.com) and/or Interchim, Cedex, France(www.interchim.com), or may be prepared using standard techniques.Myriad textbook references teaching suitable synthetic methods areprovided infra.

In still another exemplary embodiment, the 2,4-pyrimidinediaminecompounds of the invention may be synthesized from substituted orunsubstituted 2-amino-4-pyrimidinols as illustrated in Scheme (III),below:

In Scheme (III), R², R⁴, R⁵, R⁶, L¹, L² and X are as previously definedfor Scheme (I) and Z is a leaving group as discussed in more detail inconnection with Scheme IV, infra. Referring to Scheme (III),2-amino-4-pyrimidinol 30 is reacted with amine 6 (or optionallyprotected amine 21) to yield N2-substituted-4-pyrimidinol 32, which isthen halogenated as previously described to yieldN2-substituted-4-halo-2-pyrimidineamine 34. Optional deprotection (forexample if protected amine 21 was used in the first step) followed byreaction with amine 10 affords a 2,4-pyrimidinediamine according tostructural formula (I). Alternatively, pyrimidinol 30 can be reactedwith acylating agent 31.

Suitable commercially-available 2-amino-4-pyrimidinols 30 that can beused as starting materials in Scheme (III) include, but are not limitedto, 2-amino-6-chloro-4-pyrimidinol hydrate (Aldrich #A4702-8; CASRegistry 00000-00-0) and 2-amino-6-hydroxy-4-pyrimidinol (Aldrich#A5040-1; CAS Registry 56-09-7). Other 2-amino-4-pyrimidinols 30 usefulas starting materials in Scheme (III) are available from GeneralIntermediates of Canada, Inc., Edmonton, CA(www.generalintermediates.com) and/or Interchim, Cedex, France(www.interchim.com), or may be prepared using standard techniques.Myriad textbook references teaching suitable synthetic methods areprovided infra.

Alternatively, the 2,4-pyrimidinediamine compounds of the invention maybe prepared from substituted or unsubstituted 4-amino-2-pyrimidinols asillustrated in Scheme (IV), below:

In Scheme (IV), R², R⁴, R⁵, R⁶, L¹ and L² are as previously defined forScheme (I) and Z represents a leaving group. Referring to Scheme (IV),the C2-hydroxyl of 4-amino-2-pyrimidinol 40 is more reactive towardsnucleophiles than the C4-amino such that reaction with amine 6 yieldsN2-substituted-2,4-pyrimidinediamine 42. Subsequent reaction withcompound 44, which includes a good leaving group Z, or amine 10 yields a2,4-pyrimidinediamine according to structural formula (I). Compound 44may include virtually any leaving group that can be displaced by theC4-amino of N2-substituted-2,4-pyrimidinediamine 42. Suitable leavinggroups Z include, but are not limited to, halogens, methanesulfonyloxy(mesyloxy; “OMs”), trifluoromethanesulfonyloxy (“OTf”) andp-toluenesulfonyloxy (tosyloxy; “OTs”), benzene sulfonyloxy (“besylate”)and metanitro benzene sulfonyloxy (“nosylate”). Other suitable leavinggroups will be apparent to those of skill in the art.

Substituted 4-amino-2-pyrimidinol starting materials may be obtainedcommercially or synthesized using standard techniques. Myriad textbookreferences teaching suitable synthetic methods are provided infra.

In still another exemplary embodiment, the 2,4-pyrimidinediaminecompounds of the invention can be prepared from2-chloro-4-aminopyrimidines or 2-amino-4-chloropyrimidines asillustrated in Scheme (V), below:

In Scheme (V), R², R⁴, R⁵, R⁶, L¹, L² and X are as defined for Scheme(I) and Z is as defined for Scheme (IV). Referring to Scheme (V),2-amino-4-chloropyrimidine 50 is reacted with amino 10 to yield4N-substituted-2-pyrimidineamine 52 which, following reaction withcompound 31 or amine 6, yields a 2,4-pyrimidinediamine according tostructural formula (I). Alternatively, 2-chloro-4-amino-pyrimidine 54may be reacted with compound 44 followed by amine 6 to yield a compoundaccording to structural formula (I).

A variety of pyrimidines 50 and 54 suitable for use as startingmaterials in Scheme (V) are commercially available, including by way ofexample and not limitation, 2-amino-4,6-dichloropyrimidine (Aldrich#A4860-1; CAS Registry 56-05-3); 2-amino-4-chloro-6-methoxy-pyrimidine(Aldrich #51,864-6; CAS Registry 5734-64-5);2-amino-4-chloro-6-methylpyrimidine (Aldrich #12,288-2; CAS Registry5600-21-5); and 2-amino-4-chloro-6-methylthiopyrimidine (Aldrich#A4600-5; CAS Registry 1005-38-5). Additional pyrimidine startingmaterials are available from General Intermediates of Canada, Inc.,Edmonton, CA (www.generalintermediates.com) and/or Interchim, Cedex,France (www.interchim.com), or may be prepared using standardtechniques. Myriad textbook references teaching suitable syntheticmethods are provided infra.

Alternatively, 4-chloro-2-pyrimidineamines 50 may be prepared asillustrated in Scheme (Va):

In Scheme (Va), R⁵ and R⁶ are as previously defined for structuralformula (I). In Scheme (Va), dicarbonyl 53 is reacted with guanidine toyield 2-pyrimidineamine 51. Reaction with peracids likem-chloroperbenzoic acid, trifluoroperacetic acid or urea hydrogenperoxide complex yields N-oxide 55, which is then halogenated to give4-chloro-2-pyrimidineamine 50. The corresponding4-halo-2-pyrimidineamines may be obtained by using suitable halogenationreagents.

In yet another exemplary embodiment, the 2,4-pyrimidinediamine compoundsof the invention can be prepared from substituted or unsubstituteduridines as illustrated in Scheme (VI), below:

In Scheme (VI), R², R⁴, R⁵, R⁶, L¹, L² and X are as previously definedfor Scheme (I) and the superscript PG represents a protecting group, asdiscussed in connection with Scheme (IIb). According to Scheme (VI),uridine 60 has a C4 reactive center such that reaction with amine 10 orprotected amine 21 yields N4-substituted cytidine 62 or 64,respectively. Acid-catalyzed deprotection of N4-substituted 62 or 64(when “PG” represents an acid-labile protecting group) yieldsN4-substituted cytosine 28, which may be subsequently halogenated at theC2-position and reacted with amine 6 to yield a 2,4-pyrimidinediamineaccording to structural formula (I).

Cytidines may also be used as starting materials in an analogous manner,as illustrated in Scheme (VII), below:

In Scheme (VII), R², R⁴, R⁵, R⁶, L¹, L² and X are as previously definedin Scheme (I) and the superscript PG represents a protecting group asdiscussed above. Referring to Scheme (VII), like uridine 60, cytidine 70has a C4 reactive center such that reaction with amine 10 or protectedamine 21 yields N4-substituted cytidine 62 or 64, respectively. Thesecytidines 62 and 64 are then treated as previously described for Scheme(VI) to yield a 2,4-pyrimidinediamine according to structural formula(I).

Although Schemes (VI) and (VII) are exemplified with ribosylnucleosides,skilled artisans will appreciate that the corresponding 2′-deoxyribo and2′,3′-dideoxyribo nucleosides, as well as nucleosides including sugarsor sugar analogs other than ribose, would also work.

Numerous uridines and cytidines useful as starting materials in Schemes(VI) and (VII) are known in the art, and include, by way of example andnot limitation, 5-trifluoromethyl-2′-deoxycytidine (Chem. Sources #ABCRF07669; CAS Registry 66,384-66-5); 5-bromouridine (Chem. Sources Int'l2000; CAS Registry 957-75-5); 5-iodo-2′-deoxyuridine (Aldrich #1-775-6;CAS Registry 54-42-2); 5-fluorouridine (Aldrich #32,937-1; CAS Registry316-46-1); 5-iodouridine (Aldrich #85,259-7; CAS Registry 1024-99-3);5-(trifluoromethyl)uridine (Chem. Sources Int'l 2000; CAS Registry70-00-8); 5-trifluoromethyl-2′-deoxyuridine (Chem. Sources Int'l 2000;CAS Registry 70-00-8). Additional uridines and cytidines that can beused as starting materials in Schemes (VI) and (VII) are available fromGeneral Intermediates of Canada, Inc., Edmonton, CA(www.generalintermediates.com) and/or Interchim, Cedex, France(www.interchim.com), or may be prepared using standard techniques.Myriad textbook references teaching suitable synthetic methods areprovided infra.

The 2,4-pyrimidinediamine compounds of the invention can also besynthesized from substituted pyrimidines, such as chloro-substitutedpyrimidines, as illustrated in Schemes (VIII) and (IX), below:

In Schemes (VIII) and (IX), R², R⁴, L¹, L² and R^(a) are as previouslydefined for structural formula (I) and “Ar” represents an aryl group.Referring to Scheme (VIII), reaction of 2,4,6-trichloropyrimidine 80(Aldrich #T5,620-0; CAS#3764-01-0) with amine 6 yields a mixture ofthree compounds: substituted pyrimidine mono-, di- and triamines 81, 82and 83, which can be separated and isolated using HPLC or otherconventional techniques. Mono- and diamines 81 and 82 may be furtherreacted with amines 6 and/or 10 to yieldN2,N4,N6-trisubstituted-2,4,6-pyrimidinetriamines 84 and 85,respectively.

N2,N4-bis-substituted-2,4-pyrimidinediamines can be prepared in a manneranalogous to Scheme (VIII) by employing 2,4-dichloro-5-methylpyrimidineor 2,4-dichloro-pyrimidine as starting materials. In this instance, themono-substituted pyrimidineamine corresponding to compound 81 is notobtained. Instead, the reaction proceeds to yield theN2,N4-bis-substituted-2,4-pyrimidinediamine directly.

Referring to Scheme (IX), 2,4,5,6-tetrachloropyrimidine 90 (Aldrich#24,671-9; CAS#1780-40-1) is reacted with excess amine 6 to yield amixture of three compounds: 91, 92, and 93, which can be separated andisolated using HPLC or other conventional techniques. As illustrated,N2,N4-bis-substituted-5,6,-dichloro-2,4-pyrimidinediamine 92 may befurther reacted at the C6 halide with, for example a nucleophilic agent94 to yield compound 95. Alternatively, compound 92 can be convertedinto N2,N4-bis-sub situted-5-chloro-6-aryl-2,4-pyrimidinediamine 97 viaa Suzuki reaction. 2,4-Pyrimidinediamine 95 may be converted to2,4-pyrimidinediamine 99 by reaction with Bn₃SnH.

As will be recognized by skilled artisans, 2,4-pyrimidinediaminesaccording to the invention, synthesized via the exemplary methodsdescribed above or by other well-known means, may also be utilized asstarting materials and/or intermediates to synthesize additional2,4-pyrimidinediamine compounds of the invention. A specific example isillustrated in Scheme (X), below:

In Scheme (X), R⁴, R⁵, R⁶, L² and R^(a) are as previously defined forstructural formula (I). Each R^(a′) is independently an R^(a), and maybe the same or different from the illustrated R^(a). Referring to Scheme(X), carboxylic acid or ester 100 may be converted to amide 104 byreaction with amine 102. In amine 102, R^(a′) may be the same ordifferent than R^(a) of acid or ester 100. Similarly, carbonate ester106 may be converted to carbamate 108.

A second specific example is illustrated in Scheme (XI), below:

In Scheme (XI), R⁴, R⁵, R⁶, L² and R are as previously defined forstructural formula (I). Referring to Scheme (XI), amide 110 or 116 maybe converted to amine 114 or 118, respectively, by borane reduction withborane methylsulfide complex 112. Other suitable reactions forsynthesizing 2,4-pyrimidinediamine compounds from 2,4-pyrimidinediaminestarting materials will be apparent to those of skill in the art.

Although many of the synthetic schemes discussed above do not illustratethe use of protecting groups, skilled artisans will recognize that insome instances substituents R², R⁴, R⁵, R⁶, L¹ and/or L² may includefunctional groups requiring protection. The exact identity of theprotecting group used will depend upon, among other things, the identityof the functional group being protected and the reaction conditions usedin the particular synthetic scheme, and will be apparent to those ofskill in the art. Guidance for selecting protecting groups andchemistries for their attachment and removal suitable for a particularapplication can be found, for example, in Greene & Wuts, supra.

Prodrugs according to structural formula (II) may be prepared by routinemodification of the above-described methods. Alternatively, suchprodrugs may be prepared by reacting a suitably protected2,4-pyrimidinediamine of structural formula (I) with a suitableprogroup. Conditions for carrying out such reactions and fordeprotecting the product to yield a prodrug of formula (II) arewell-known.

Myriad references teaching methods useful for synthesizing pyrimidinesgenerally, as well as starting materials described in Schemes (I)-(IX),are known in the art. For specific guidance, the reader is referred toBrown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16 (Weissberger, A., Ed.), 1962, IntersciencePublishers, (A Division of John Wiley & Sons), New York (“Brown I”);Brown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16, Supplement I (Weissberger, A. and Taylor, E. C.,Ed.), 1970, Wiley-Interscience, (A Division of John Wiley & Sons), NewYork (Brown II”); Brown, D. J., “The Pyrimidines”, in The Chemistry ofHeterocyclic Compounds, Volume 16, Supplement II (Weissberger, A. andTaylor, E. C., Ed.), 1985, An Interscience Publication (John Wiley &Sons), New York (“Brown III”); Brown, D. J., “The Pyrimidines” in TheChemistry of Heterocyclic Compounds, Volume 52 (Weissberger, A. andTaylor, E. C., Ed.), 1994, John Wiley & Sons, Inc., New York, pp. 1-1509(Brown IV”); Kenner, G. W. and Todd, A., in Heterocyclic Compounds,Volume 6, (Elderfield, R. C., Ed.), 1957, John Wiley, New York, Chapter7 (pyrimidines); Paquette, L. A., Principles of Modern HeterocyclicChemistry, 1968, W. A. Benjamin, Inc., New York, pp. 1-401 (uracilsynthesis pp. 313, 315; pyrimidine synthesis pp. 313-316; aminopyrimidine synthesis pp. 315); Joule, J. A., Mills, K. and Smith, G. F.,Heterocyclic Chemistry, 3^(rd) Edition, 1995, Chapman and Hall, London,UK, pp. 1-516; Vorbruggen, H. and Ruh-Pohlenz, C., Handbook ofNucleoside Synthesis, John Wiley & Sons, New York, 2001, pp. 1-631(protection of pyrimidines by acylation pp. 90-91; silylation ofpyrimidines pp. 91-93); Joule, J. A., Mills, K. and Smith, G. F.,Heterocyclic Chemistry, 4^(th) Edition, 2000, Blackwell Science, Ltd,Oxford, UK, pp. 1-589; and Comprehensive Organic Synthesis, Volumes 1-9(Trost, B. M. and Fleming, I., Ed.), 1991, Pergamon Press, Oxford, UK.

6.4 Inhibition of Fc Receptor Signal Cascades

Active 2,4-pyrimidinediamine compounds of the invention inhibit Fcreceptor signaling cascades that lead to, among other things,degranulation of cells. As a specific example, the compounds inhibit theFcεRI and/or FcγRI signal cascades that lead to degranulation of immunecells such as neutrophil, eosinophil, mast and/or basophil cells. Bothmast and basophil cells play a central role in allergen-induceddisorders, including, for example, allergic rhinitis and asthma.Referring to FIG. 1, upon exposure allergens, which may be, among otherthings, pollen or parasites, allergen-specific IgE antibodies aresynthesized by B-cells activated by IL-4 (or IL-13) and other messengersto switch to IgE class specific antibody synthesis. Theseallergen-specific IgEs bind to the high affinity FcεRI. Upon binding ofantigen, the FcεR1-bound IgEs are cross-linked and the IgE receptorsignal transduction pathway is activated, which leads to degranulationof the cells and consequent release and/or synthesis of a host ofchemical mediators, including histamine, proteases (e.g., tryptase andchymase), lipid mediators such as leukotrienes (e.g., LTC4),platelet-activating factor (PAF) and prostaglandins (e.g., PGD2) and aseries of cytokines, including TNF-α, IL-4, IL-13, IL-5, IL-6, IL-8,GMCSF, VEGF and TGF-β. The release and/or synthesis of these mediatorsfrom mast and/or basophil cells accounts for the early and late stageresponses induced by allergens, and is directly linked to downstreamevents that lead to a sustained inflammatory state.

The molecular events in the FcεRI signal transduction pathway that leadto release of preformed mediators via degranulation and release and/orsynthesis of other chemical mediators are well-known and are illustratedin FIG. 2. Referring to FIG. 2, the FcεRI is a heterotetrameric receptorcomposed of an IgE-binding alpha-subunit, a beta subunit, and two gammasubunits (gamma homodimer). Cross-linking of FcεRI-bound IgE bymultivalent binding agents (including, for example IgE-specificallergens or anti-IgE antibodies or fragments) induces the rapidassociation and activation of the Src-related kinase Lyn. Lynphosphorylates immunoreceptor tyrosine-based activation motifs (ITAMS)on the intracellular beta and gamma subunits, which leads to therecruitment of additional Lyn to the beta subunit and Syk kinase to thegamma homodimer. These receptor-associated kinases, which are activatedby intra- and intermolecular phosphorylation, phosphorylate othercomponents of the pathway, such as the Btk kinase, LAT, andphospholipase C-gamma PLC-gamma). Activated PLC-gamma initiates pathwaysthat lead to protein kinase C activation and Ca²⁺ mobilization, both ofwhich are required for degranulation. FcεR1 cross-linking also activatesthe three major classes of mitogen activated protein (MAP) kinases, i.e.ERK1/2, JNK1/2, and p38. Activation of these pathways is important inthe transcriptional regulation of proinflammatory mediators, such asTNF-α and IL-6, as well as the lipid mediator leukotriene CA (LTC4).

Although not illustrated, the FcγRI signaling cascade is believed toshare some common elements with the FcεRI signaling cascade.Importantly, like FcεRI, the FcγRI includes a gamma homodimer that isphosphorylated and recruits Syk, and like FcεRI, activation of the FcγRIsignaling cascade leads to, among other things, degranulation. Other Fcreceptors that share the gamma homodimer, and which can be regulated bythe active 2,4-pyrimidinediamine compounds include, but are not limitedto, FcαRI and FcγRIII.

The ability of the 2,4-pyrimidinediamine compounds of the invention toinhibit Fc receptor signaling cascades may be simply determined orconfirmed in in vitro assays. Suitable assays for confirming inhibitionof FcεRI-mediated degranulation are provided in the Examples section. Inone typical assay, cells capable of undergoing FcεRI-mediateddegranulation, such as mast or basophil cells, are first grown in thepresence of IL-4, Stem Cell Factor (SCF), IL-6 and IgE to increaseexpression of the FcεRI, exposed to a 2,4-pyrimidinediamine testcompound of the invention and stimulated with anti-IgE antibodies (or,alternatively, an IgE-specific allergen). Following incubation, theamount of a chemical mediator or other chemical agent released and/orsynthesized as a consequence of activating the FcεRI signaling cascademay be quantified using standard techniques and compared to the amountof the mediator or agent released from control cells (i.e., cells thatare stimulated but that are not exposed to test compound). Theconcentration of test compound that yields a 50% reduction in thequantity of the mediator or agent measured as compared to control cellsis the IC₅₀ of the test compound. The origin of the mast or basophilcells used in the assay will depend, in part, on the desired use for thecompounds and will be apparent to those of skill in the art. Forexample, if the compounds will be used to treat or prevent a particulardisease in humans, a convenient source of mast or basophil cells is ahuman or other animal which constitutes an accepted or known clinicalmodel for the particular disease. Thus, depending upon the particularapplication, the mast or basophil cells may be derived from a widevariety of animal sources, ranging from, for example, lower mammals suchas mice and rats, to dogs, sheep and other mammals commonly employed inclinical testing, to higher mammals such as monkeys, chimpanzees andapes, to humans. Specific examples of cells suitable for carrying outthe in vitro assays include, but are not limited to, rodent or humanbasophil cells, rat basophil leukemia cell lines, primary mouse mastcells (such as bone marrow-derived mouse mast cells “BMMC”) and primaryhuman mast cells isolated from cord blood (“CHMC”) or other tissues suchas lung. Methods for isolating and culturing these cell types arewell-known or are provided in the Examples section (see, e.g., Demo etal., 1999, Cytometry 36(4):340-348 and copending application Ser. No.10/053,355, filed Nov. 8, 2001, the disclosures of which areincorporated herein by reference). Of course, other types of immunecells that degranulate upon activation of the FcεRI signaling cascademay also be used, including, for example, eosinophils.

As will be recognized by skilled artisans, the mediator or agentquantified is not critical. The only requirement is that it be amediator or agent released and/or synthesized as a consequence ofinitiating or activating the Fc receptor signaling cascade. For example,referring to FIG. 1, activation of the FcεRI signaling cascade in mastand/or basophil cells leads to numerous downstream events. For example,activation of the FcεRI signal cascade leads to the immediate release(i.e., within 1-3 min. following receptor activation) of a variety ofpreformed chemical mediators and agents via degranulation. Thus, in oneembodiment, the mediator or agent quantified may be specific to granules(i.e., present in granules but not in the cell cytoplasm generally).Examples of granule-specific mediators or agents that can be quantifiedto determine and/or confirm the activity of a 2,4-pyrimidinediaminecompound of the invention include, but are not limited to,granule-specific enzymes such as hexosaminidase and tryptase andgranule-specific components such as histamine and serotonin. Assays forquantifying such factors are well-known, and in many instances arecommercially available. For example, tryptase and/or hexosaminidaserelease may be quantified by incubating the cells with cleavablesubstrates that fluoresce upon cleavage and quantifying the amount offluorescence produced using conventional techniques. Such cleavablefluorogenic substrates are commercially available. For example, thefluorogenic substrates Z-Gly-Pro-Arg-AMC (Z=benzyloxycarbonyl;AMC=7-amino-4-methylcoumarin; BIOMOL Research Laboratories, Inc.,Plymouth Meeting, Pa. 19462, Catalog No. P-142) and Z-Ala-Lys-Arg-AMC(Enzyme Systems Products, a division of ICN Biomedicals, Inc.,Livermore, Calif. 94550, Catalog No. AMC-246) can be used to quantifythe amount of tryptase released. The fluorogenic substrate4-methylumbelliferyl-N-acetyl-3-D-glucosaminide (Sigma, St. Louis, Mo.,Catalog #69585) can be used to quantify the amount of hexosaminidasereleased. Histamine release may be quantified using a commerciallyavailable enzyme-linked immunosorbent assay (ELISA) such as Immunotechhistamine ELISA assay #IM2015 (Beckman-Coulter, Inc.). Specific methodsof quantifying the release of tryptase, hexosaminidase and histamine areprovided in the Examples section. Any of these assays may be used todetermine or confirm the activity of the 2,4-pyrimidinediamine compoundsof the invention.

Referring again to FIG. 1, degranulation is only one of severalresponses initiated by the FcεRI signaling cascade. In addition,activation of this signaling pathway leads to the de novo synthesis andrelease of cytokines and chemokines such as IL-4, IL-5, IL-6, TNF-α,IL-13 and MIP1-α), and release of lipid mediators such as leukotrienes(e.g., LTC4), platelet activating factor (PAF) and prostaglandins.Accordingly, the 2,4-pyrimidinediamine compounds of the invention mayalso be assessed for activity by quantifying the amount of one or moreof these mediators released and/or synthesized by activated cells.

Unlike the granule-specific components discussed above, these “latestage” mediators are not released immediately following activation ofthe FcεRI signaling cascade. Accordingly, when quantifying these latestage mediators, care should be taken to insure that the activated cellculture is incubated for a time sufficient to result in the synthesis(if necessary) and release of the mediator being quantified. Generally,PAF and lipid mediators such as leukotriene C4 are released 3-30 min.following FcεRI activation. The cytokines and other late stage mediatorsare released approx. 4-8 hrs. following FcεRI activation. Incubationtimes suitable for a specific mediator will be apparent to those ofskill in the art. Specific guidance and assays are provided in theExamples section.

The amount of a particular late stage mediator released may bequantified using any standard technique. In one embodiment, theamount(s) may be quantified using ELISA assays. ELISA assay kitssuitable for quantifying the amount of TNFα, IL-4, IL-5, IL-6 and/orIL-13 released are available from, for example, Biosource International,Inc., Camarillo, Calif. 93012 (see, e.g., Catalog Nos. KHC3011, KHC0042,KHC0052, KHC0061 and KHC0132). ELISA assay kits suitable for quantifyingthe amount of leukotriene C4 (LTC4) released from cells are availablefrom Cayman Chemical Co., Ann Arbor, Mich. 48108 (see, e.g., Catalog No.520211).

Typically, active 2,4-pyrimidinediamine compounds of the invention willexhibit IC₅₀s with respect to FcεRI-mediated degranulation and/ormediator release or synthesis of about 20 μM or lower, as measured in anin vitro assay, such as one of the in vitro assays described above or inthe Examples section. Of course, skilled artisans will appreciate thatcompounds which exhibit lower IC₅₀s, for example on the order of 10 μM,1 μM, 100 nM, 10 nM, 1 nM, or even lower, are particularly useful.

Skilled artisans will also appreciate that the various mediatorsdiscussed above may induce different adverse effects or exhibitdifferent potencies with respect to the same adverse effect. Forexample, the lipid mediator LTC4 is a potent vasoconstrictor—it isapproximately 1000-fold more potent at inducing vasoconstriction thanhistamine. As another example, in addition to mediating atopic or Type Ihypersensitivity reactions, cytokines can also cause tissue remodelingand cell proliferation. Thus, although compounds that inhibit releaseand/or synthesis of any one of the previously discussed chemicalmediators are useful, skilled artisans will appreciate that compoundswhich inhibit the release and/or synthesis of a plurality, or even all,of the previously described mediators find particular use, as suchcompounds are useful for ameliorating or avoiding altogether aplurality, or even all, of the adverse effects induced by the particularmediators. For example, compounds which inhibit the release of all threetypes of mediators-granule-specific, lipid and cytokine—are useful fortreating or preventing immediate Type I hypersensitivity reactions aswell as the chronic symptoms associated therewith.

Compounds of the invention capable of inhibiting the release of morethan one type of mediator (e.g., granule-specific or late stage) may beidentified by determining the IC₅₀ with respect to a mediatorrepresentative of each class using the various in vitro assays describedabove (or other equivalent in vitro assays). Compounds of the inventionwhich are capable of inhibiting the release of more than one mediatortype will typically exhibit an IC₅₀ for each mediator type tested ofless than about 20 μM. For example, a compound which exhibits an IC₅₀ of1 μM with respect to histamine release (IC₅₀ ^(histamine)) and an IC₅₀of 1 nM with respect to leukotriene LTC4 synthesis and/or release (IC₅₀^(LTC4)) inhibits both immediate (granule-specific) and late stagemediator release. As another specific example, a compound that exhibitsan IC₅₀ ^(tryptase) of 10 μM, an IC₅₀ ^(LT)C4 of 1 μM and an IC₅₀ ^(IL4)of 1 μM inhibits immediate (granule-specific), lipid and cytokinemediator release. Although the above specific examples utilize the IC₅₀sof one representative mediator of each class, skilled artisans willappreciate that the IC₅₀s of a plurality, or even all, mediatorscomprising one or more of the classes may be obtained. The quantity(ies)and identity(ies) of mediators for which IC₅₀ data should be ascertainedfor a particular compound and application will be apparent to those ofskill in the art.

Similar assays may be utilized to confirm inhibition of signaltransduction cascades initiated by other Fc receptors, such as FcαRI,FcγRI and/or FcγRIII signaling, with routine modification. For example,the ability of the compounds to inhibit FcγRI signal transduction may beconfirmed in assays similar to those described above, with the exceptionthat the FcγRI signaling cascade is activated, for example by incubatingthe cells with IgG and an IgG-specific allergen or antibody, instead ofIgE and an IgE-specific allergen or antibody. Suitable cell types,activating agents and agents to quantify to confirm inhibition of otherFc receptors, such as Fc receptors that comprise a gamma homodimer, willbe apparent to those of skill in the art.

One particularly useful class of compounds includes those2,4-pyrimidinediamine compounds that inhibit the release of immediategranule-specific mediators and late stage mediators with approximatelyequivalent IC₅₀s. By approximately equivalent is meant that the IC₅₀sfor each mediator type are within about a 10-fold range of one another.Another particularly useful class of compounds includes those2,4-pyrimidinediamine compounds that inhibit the release of immediategranule-specific mediators, lipid mediators and cytokine mediators withapproximately equivalent IC₅₀s. In a specific embodiment, such compoundsinhibit the release of the following mediators with approximatelyequivalent IC₅₀s: histamine, tryptase, hexosaminidase, IL-4, IL-5, IL-6,IL-13, TNFα and LTC4. Such compounds are particularly useful for, amongother things, ameliorating or avoiding altogether both the early andlate stage responses associated with atopic or immediate Type Ihypersensitivity reactions.

Ideally, the ability to inhibit the release of all desired types ofmediators will reside in a single compound. However, mixtures ofcompounds can also be identified that achieve the same result. Forexample, a first compound which inhibits the release of granule specificmediators may be used in combination with a second compound whichinhibits the release and/or synthesis of cytokine mediators.

In addition to the FcεRI or FcγRI degranulation pathways discussedabove, degranulation of mast and/or basophil cells can be induced byother agents. For example, ionomycin, a calcium ionophore that bypassesthe early FcεRI or FcγRI signal transduction machinery of the cell,directly induces a calcium flux that triggers degranulation. Referringagain to FIG. 2, activated PLCγ initiates pathways that lead to, amongother things, calcium ion mobilization and subsequent degranulation. Asillustrated, this Ca²⁺ mobilization is triggered late in the FcεRIsignal transduction pathway. As mentioned above, and as illustrated inFIG. 3, ionomycin directly induces Ca²⁺ mobilization and a Ca²⁺ fluxthat leads to degranulation. Other ionophores that induce degranulationin this manner include A23187. The ability of granulation-inducingionophores such as ionomycin to bypass the early stages of the FcεRIand/or FcγRI signaling cascades may be used as a counter screen toidentify active compounds of the invention that specifically exert theirdegranulation-inhibitory activity by blocking or inhibiting the earlyFcεRI or FcγRI signaling cascades, as discussed above. Compounds whichspecifically inhibit such early FcεRI or FcγRI-mediated degranulationinhibit not only degranulation and subsequent rapid release ofhistamine, tryptase and other granule contents, but also inhibit thepro-inflammatory activation pathways causing the release of TNFα, IL-4,IL-13 and the lipid mediators such as LTC4. Thus, compounds whichspecifically inhibit such early FcεRI and/or FcγRI-mediateddegranulation block or inhibit not only acute atopic or Type Ihypersensitivity reactions, but also late responses involving multipleinflammatory mediators.

Compounds of the invention that specifically inhibit early FcεRI and/orFcγRI-mediated degranulation are those compounds that inhibit FcεRIand/or FcγRI-mediated degranulation (for example, have an IC₅₀ of lessthan about 20 μM with respect to the release of a granule-specificmediator or component as measured in an in vitro assay with cellsstimulated with an IgE or IgG binding agent) but that do not appreciablyinhibit ionophore-induced degranulation. In one embodiment, compoundsare considered to not appreciably inhibit ionophore-induceddegranulation if they exhibit an IC₅₀ of ionophore-induced degranulationof greater than about 20 μM, as measured in an in vitro assay. Ofcourse, active compounds that exhibit even higher IC₅₀s ofionophore-induced degranulation, or that do not inhibitionophore-induced degranulation at all, are particularly useful. Inanother embodiment, compounds are considered to not appreciably inhibitionophore-induced degranulation if they exhibit a greater than 10-folddifference in their IC₅₀s of FcεRI and/or FcγRI-mediated degranulationand ionophore-induced degranulation, as measured in an in vitro assay.Assays suitable for determining the IC₅₀ of ionophore-induceddegranulation include any of the previously-described degranulationassays, with the modification that the cells are stimulated or activatedwith a degranulation-inducing calcium ionophore such as ionomycin orA23187 (A.G. Scientific, San Diego, Calif.) instead of anti-IgEantibodies or an IgE-specific allergen. Specific assays for assessingthe ability of a particular 2,4-pyrimidinediamine compound of theinvention to inhibit ionophore-induced degranulation are provided in theExamples section.

As will be recognized by skilled artisans, compounds which exhibit ahigh degree of selectivity of FcεRI-mediated degranulation findparticular use, as such compounds selectively target the FcεRI cascadeand do not interfere with other degranulation mechanisms. Similarly,compounds which exhibit a high degree of selectivity of FcγRI-mediateddegranulation find particular use, as such compounds selectively targetthe FcγRI cascade and do not interfere with other degranulationmechanisms. Compounds which exhibit a high degree of selectivity aregenerally 10-fold or more selective for FcεRI- or FcγRI-mediateddegranulation over ionophore-induced degranulation, such asionomycin-induced degranulation.

Biochemical and other data confirm that the 2,4-pyrimidinediaminecompounds described herein are potent inhibitors of Syk kinase activity.For example, in experiments with an isolated Syk kinase, of twenty four2,4-pyrimidinediamine compounds tested, all but two inhibited the Sykkinase catalyzed phosphorylation of a peptide substrate with IC50s inthe submicromolar range. The remaining compounds inhibitedphosphorylation in the micromolar range. In addition, of sixteencompounds tested in an in vitro assay with mast cells, all inhibitedphosphorylation of Syk kinase substrates (e.g., PLC-gamma1, LAT) andproteins downstream of Syk kinase (e.g., JNK, p38, Erkl/2 and PKB, whentested), but not proteins upstream of Syk kinase in the cascade (e.g.,Lyn). Phosphorylation of Lyn substrates was not inhibited by the2,4-pyrimidinediamine compounds tested. Moreover, for the followingcompounds, a high correlation was observed between their inhibition ofSyk kinase activity in biochemical assays (IC₅₀s in the range of 3 to1850 nM) and their inhibition of FcεR1-mediated degranulation in mastcells (IC₅₀s in the range of 30 to 1650 nM): R950373, R950368, R921302,R945371, R945370, R945369, R945365, R921304, R945144, R945140, R945071,R940358, R940353, R940352, R940351, R940350, R940347, R921303, R940338,R940323, R940290, R940277, R940276, R940275, R940269, R940255, R935393,R935372, R935366, R935310, R935309, R935307, R935304, R935302, R935293,R935237, R935198, R935196, R935194, R935193, R935191, R935190, R935138,R927050, R926968, R926956, R926931, R926891, R926839, R926834, R926816,R926813, R926791, R926782, R926780, R926757, R926753, R926745, R926715,R926508, R926505, R926502, R926501, R926500, R921218, R921147, R920410,R909268, R921219, R908712, R908702.

Accordingly, the activity of the 2,4-pyrimidinediamine compounds of theinvention may also be confirmed in biochemical or cellular assays of Sykkinase activity. Referring again to FIG. 2, in the FcεRI signalingcascade in mast and/or basophil cells, Syk kinase phosphorylates LAT andPLC-gamma1, which leads to, among other things, degranulation. Any ofthese activities may be used to confirm the activity of the2,4-pyrimidinediamine compounds of the invention. In one embodiment, theactivity is confirmed by contacting an isolated Syk kinase, or an activefragment thereof with a 2,4-pyrimidinediamine compound in the presenceof a Syk kinase substrate (e.g., a synthetic peptide or a protein thatis known to be phophorylated by Syk in a signaling cascade) andassessing whether the Syk kinase phosphorylated the substrate.

Alternatively, the assay may be carried out with cells that express aSyk kinase. The cells may express the Syk kinase endogenously or theymay be engineered to express a recombinant Syk kinase. The cells mayoptionally also express the Syk kinase substrate. Cells suitable forperforming such confirmation assays, as well as methods of engineeringsuitable cells will be apparent to those of skill in the art. Specificexamples of biochemical and cellular assays suitable for confirming theactivity of the 2,4-pyrimidinediamine compounds are provided in theExamples section.

Generally, compounds that are Syk kinase inhibitors will exhibit an IC₅₀with respect to a Syk kinase activity, such as the ability of Syk kinaseto phosphorylate a synthetic or endogenous substrate, in an in vitro orcellular assay in the range of about 20 μM or less. Skilled artisanswill appreciate that compounds that exhibit lower IC50s, such as in therange of 10 μM, 1 μM, 100 nM, 10 nM, 1 nM, or even lower, areparticularly useful.

6.5 Uses and Compositions

As previously discussed, the active compounds of the invention inhibitFc receptor signaling cascades, especially those Fc receptors includinga gamma homodimer, such as the FcεRI and/or FcγRI signaling cascades,that lead to, among other things, the release and/or synthesis ofchemical mediators from cells, either via degranulation or otherprocesses. As also discussed, the active compounds are also potentinhibitors of Syk kinase. As a consequence of these activities, theactive compounds of the invention may be used in a variety of in vitro,in vivo and ex vivo contexts to regulate or inhibit Syk kinase,signaling cascades in which Syk kinase plays a role, Fc receptorsignaling cascades, and the biological responses effected by suchsignaling cascades. For example, in one embodiment, the compounds may beused to inhibit Syk kinase, either in vitro or in vivo, in virtually anycell type expressing Syk kinase. They may also be used to regulatesignal transduction cascades in which Syk kinase plays a role. SuchSyk-dependent signal transduction cascades include, but are not limitedto, the FcεRI, FcγRI, FcγRIII, BCR and integrin signal transductioncascades. The compounds may also be used in vitro or in vivo toregulate, and in particular inhibit, cellular or biological responseseffected by such Syk-dependent signal transduction cascades. Suchcellular or biological responses include, but are not limited to,respiratory burst, cellular adhesion, cellular degranulation, cellspreading, cell migration, cell aggregation, phagcytosis, cytokinesynthesis and release, cell maturation and Ca²⁺ flux. Importantly, thecompounds may be used to inhibit Syk kinase in vivo as a therapeuticapproach towards the treatment or prevention of diseases mediated,either wholly or in part, by a Syk kinase activity. Non-limitingexamples of Syk kinase mediated diseases that may be treated orprevented with the compounds are those discussed in more detail, below.

In another embodiment, the active compounds may be used to regulate orinhibit the Fc receptor signaling cascades and/or FcεRI- and/orFcγRI-mediated degranulation as a therapeutic approach towards thetreatment or prevention of diseases characterized by, caused by and/orassociated with the release or synthesis of chemical mediators of suchFc receptor signaling cascades or degranulation. Such treatments may beadministered to animals in veterinary contexts or to humans. Diseasesthat are characterized by, caused by or associated with such mediatorrelease, synthesis or degranulation, and that can therefore be treatedor prevented with the active compounds include, by way of example andnot limitation, atopy or anaphylactic hypersensitivity or allergicreactions, allergies (e.g., allergic conjunctivitis, allergic rhinitis,atopic asthma, atopic dermatitis and food allergies), low grade scarring(e.g., of scleroderma, increased fibrosis, keloids, post-surgical scars,pulmonary fibrosis, vascular spasms, migraine, reperfusion injury andpost myocardial infarction), diseases associated with tissue destruction(e.g., of COPD, cardiobronchitis and post myocardial infarction),diseases associated with tissue inflammation (e.g., irritable bowelsyndrome, spastic colon and inflammatory bowel disease), inflammationand scarring.

When used to treat or prevent such diseases, the active compounds may beadministered singly, as mixtures of one or more active compounds or inmixture or combination with other agents useful for treating suchdiseases and/or the symptoms associated with such diseases. The activecompounds may also be administered in mixture or in combination withagents useful to treat other disorders or maladies, such as steroids,membrane stabilizers, 5LO inhibitors, leukotriene synthesis and receptorinhibitors, inhibitors of IgE isotype switching or IgE synthesis, IgGisotype switching or IgG synthesis, β-agonists, tryptase inhibitors,aspirin, COX inhibitors, methotrexate, anti-TNF drugs, retuxin, PD4inhibitors, p38 inhibitors, PDE4 inhibitors, and antihistamines, to namea few. The active compounds may be administered per se in the form ofprodrugs or as pharmaceutical compositions, comprising an activecompound or prodrug.

Pharmaceutical compositions comprising the active compounds of theinvention (or prodrugs thereof) may be manufactured by means ofconventional mixing, dissolving, granulating, dragee-making levigating,emulsifying, encapsulating, entrapping or lyophilization processes. Thecompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients or auxiliarieswhich facilitate processing of the active compounds into preparationswhich can be used pharmaceutically.

The active compound or prodrug may be formulated in the pharmaceuticalcompositions per se, or in the form of a hydrate, solvate, N-oxide orpharmaceutically acceptable salt, as previously described. Typically,such salts are more soluble in aqueous solutions than the correspondingfree acids and bases, but salts having lower solubility than thecorresponding free acids and bases may also be formed.

Pharmaceutical compositions of the invention may take a form suitablefor virtually any mode of administration, including, for example,topical, ocular, oral, buccal, systemic, nasal, injection, transdermal,rectal, vaginal, etc., or a form suitable for administration byinhalation or insufflation.

For topical administration, the active compound(s) or prodrug(s) may beformulated as solutions, gels, ointments, creams, suspensions, etc. asare well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection, as well as those designed for transdermal,transmucosal oral or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions oremulsions of the active compound(s) in aqueous or oily vehicles. Thecompositions may also contain formulating agents, such as suspending,stabilizing and/or dispersing agent. The formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multidosecontainers, and may contain added preservatives.

Alternatively, the injectable formulation may be provided in powder formfor reconstitution with a suitable vehicle, including but not limited tosterile pyrogen free water, buffer, dextrose solution, etc., before use.To this end, the active compound(s) may be dried by any art-knowntechnique, such as lyophilization, and reconstituted prior to use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are knownin the art.

For oral administration, the pharmaceutical compositions may take theform of, for example, lozenges, tablets or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); or wetting agents (e.g., sodiumlauryl sulfate). The tablets may be coated by methods well known in theart with, for example, sugars, films or enteric coatings. Compoundswhich are particularly suitable for oral administration includeCompounds R940350, R935372, R935193, R927050 and R935391. Liquidpreparations for oral administration may take the form of, for example,elixirs, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters, ethyl alcohol, Cremophore™ orfractionated vegetable oils); and preservatives (e.g., methyl orpropyl-p-hydroxybenzoates or sorbic acid). The preparations may alsocontain buffer salts, preservatives, flavoring, coloring and sweeteningagents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound or prodrug, as is well known.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For rectal and vaginal routes of administration, the active compound(s)may be formulated as solutions (for retention enemas) suppositories orointments containing conventional suppository bases such as cocoa butteror other glycerides.

For nasal administration or administration by inhalation orinsufflation, the active compound(s) or prodrug(s) can be convenientlydelivered in the form of an aerosol spray from pressurized packs or anebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit maybe determined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator (for examplecapsules and cartridges comprised of gelatin) may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

A specific example of an aqueous suspension formulation suitable fornasal administration using commercially-available nasal spray devicesincludes the following ingredients: active compound or prodrug (0.5-20mg/ml); benzalkonium chloride (0.1-0.2 mg/mL); polysorbate 80 (TWEEN®80; 0.5-5 mg/ml); carboxymethylcellulose sodium or microcrystallinecellulose (1-15 mg/ml); phenylethanol (1-4 mg/ml); and dextrose (20-50mg/ml). The pH of the final suspension can be adjusted to range fromabout pH5 to pH7, with a pH of about pH 5.5 being typical.

Another specific example of an aqueous suspension suitable foradministration of the compounds via inhalation, and in particular forsuch administration of Compound R921218, contains 1-20 mg/mL Compound orprodrug, 0.1-1% (v/v) Polysorbate 80 (TWEEN®80), 50 mM citrate and/or0.9% sodium chloride.

For ocular administration, the active compound(s) or prodrug(s) may beformulated as a solution, emulsion, suspension, etc. suitable foradministration to the eye. A variety of vehicles suitable foradministering compounds to the eye are known in the art. Specificnon-limiting examples are described in U.S. Pat. Nos. 6,261,547;6,197,934; 6,056,950; 5,800,807; 5,776,445; 5,698,219; 5,521,222;5,403,841; 5,077,033; 4,882,150; and 4,738,851.

For prolonged delivery, the active compound(s) or prodrug(s) can beformulated as a depot preparation for administration by implantation orintramuscular injection. The active ingredient may be formulated withsuitable polymeric or hydrophobic materials (e.g., as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly solublederivatives, e.g., as a sparingly soluble salt. Alternatively,transdermal delivery systems manufactured as an adhesive disc or patchwhich slowly releases the active compound(s) for percutaneous absorptionmay be used. To this end, permeation enhancers may be used to facilitatetransdermal penetration of the active compound(s). Suitable transdermalpatches are described in for example, U.S. Pat. Nos. 5,407,713;5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189;5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475.

Alternatively, other pharmaceutical delivery systems may be employed.Liposomes and emulsions are well-known examples of delivery vehiclesthat may be used to deliver active compound(s) or prodrug(s). Certainorganic solvents such as dimethylsulfoxide (DMSO) may also be employed,although usually at the cost of greater toxicity.

The pharmaceutical compositions may, if desired, be presented in a packor dispenser device which may contain one or more unit dosage formscontaining the active compound(s). The pack may, for example, comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration.

6.6 Effective Dosages

The active compound(s) or prodrug(s) of the invention, or compositionsthereof, will generally be used in an amount effective to achieve theintended result, for example in an amount effective to treat or preventthe particular disease being treated. The compound(s) may beadministered therapeutically to achieve therapeutic benefit orprophylactically to achieve prophylactic benefit. By therapeutic benefitis meant eradication or amelioration of the underlying disorder beingtreated and/or eradication or amelioration of one or more of thesymptoms associated with the underlying disorder such that the patientreports an improvement in feeling or condition, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forexample, administration of a compound to a patient suffering from anallergy provides therapeutic benefit not only when the underlyingallergic response is eradicated or ameliorated, but also when thepatient reports a decrease in the severity or duration of the symptomsassociated with the allergy following exposure to the allergen. Asanother example, therapeutic benefit in the context of asthma includesan improvement in respiration following the onset of an asthmaticattack, or a reduction in the frequency or severity of asthmaticepisodes. Therapeutic benefit also includes halting or slowing theprogression of the disease, regardless of whether improvement isrealized.

For prophylactic administration, the compound may be administered to apatient at risk of developing one of the previously described diseases.For example, if it is unknown whether a patient is allergic to aparticular drug, the compound may be administered prior toadministration of the drug to avoid or ameliorate an allergic responseto the drug. Alternatively, prophylactic administration may be appliedto avoid the onset of symptoms in a patient diagnosed with theunderlying disorder. For example, a compound may be administered to anallergy sufferer prior to expected exposure to the allergen. Compoundsmay also be administered prophylactically to healthy individuals who arerepeatedly exposed to agents known to one of the above-describedmaladies to prevent the onset of the disorder. For example, a compoundmay be administered to a healthy individual who is repeatedly exposed toan allergen known to induce allergies, such as latex, in an effort toprevent the individual from developing an allergy. Alternatively, acompound may be administered to a patient suffering from asthma prior topartaking in activities which trigger asthma attacks to lessen theseverity of, or avoid altogether, an asthmatic episode.

The amount of compound administered will depend upon a variety offactors, including, for example, the particular indication beingtreated, the mode of administration, whether the desired benefit isprophylactic or therapeutic, the severity of the indication beingtreated and the age and weight of the patient, the bioavailability ofthe particular active compound, etc. Determination of an effectivedosage is well within the capabilities of those skilled in the art.

Effective dosages may be estimated initially from in vitro assays. Forexample, an initial dosage for use in animals may be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an IC₅₀ of the particular compound as measured in asin vitro assay, such as the in vitro CHMC or BMMC and other in vitroassays described in the Examples section. Calculating dosages to achievesuch circulating blood or serum concentrations taking into account thebioavailability of the particular compound is well within thecapabilities of skilled artisans. For guidance, the reader is referredto Fingl & Woodbury, “General Principles,” In. Goodman and Gilman's ThePharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latestedition, Pagamonon Press, and the references cited therein.

Initial dosages can also be estimated from in vivo data, such as animalmodels. Animal models useful for testing the efficacy of compounds totreat or prevent the various diseases described above are well-known inthe art. Suitable animal models of hypersensitivity or allergicreactions are described in Foster, 1995, Allergy 50(21 Suppl):6-9,discussion 34-38 and Tumas et al., 2001, J. Allergy Clin. Immunol.107(6):1025-1033. Suitable animal models of allergic rhinitis aredescribed in Szelenyi et al., 2000, Arzneimittelforschung50(11):1037-42; Kawaguchi et al., 1994, Clin. Exp. Allergy 24(3):238-244and Sugimoto et al., 2000, Immunopharmacology 48(1): 1-7. Suitableanimal models of allergic conjunctivitis are described in Carreras etal., 1993, Br. J. Ophthalmol. 77(8):509-514; Saiga et al., 1992,Ophthalmic Res. 24(1):45-50; and Kunert et al., 2001, Invest.Ophthalmol. Vis. Sci. 42(11):2483-2489. Suitable animal models ofsystemic mastocytosis are described in O'Keefe et al., 1987, J. Vet.Intern. Med. 1(2):75-80 and Bean-Knudsen et al., 1989, Vet. Pathol.26(1):90-92. Suitable animal models of hyper IgE syndrome are describedin Claman et al., 1990, Clin. Immunol. Immunopathol. 56(1):46-53.Suitable animal models of B-cell lymphoma are described in Hough et al.,1998, Proc. Natl. Acad. Sci. USA 95:13853-13858 and Hakim et al., 1996,J. Immunol. 157(12):5503-5511. Suitable animal models of atopicdisorders such as atopic dermatitis, atopic eczema and atopic asthma aredescribed in Chan et al., 2001, J. Invest. Dermatol. 117(4):977-983 andSuto et al., 1999, Int. Arch. Allergy Immunol. 120 (Suppl 1):70-75.Ordinarily skilled artisans can routinely adapt such information todetermine dosages suitable for human administration. Additional suitableanimal models are described in the Examples section.

Dosage amounts will typically be in the range of from about 0.0001 or0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but may be higher orlower, depending upon, among other factors, the activity of thecompound, its bioavailability, the mode of administration and variousfactors discussed above. Dosage amount and interval may be adjustedindividually to provide plasma levels of the compound(s) which aresufficient to maintain therapeutic or prophylactic effect. For example,the compounds may be administered once per week, several times per week(e.g., every other day), once per day or multiple times per day,depending upon, among other things, the mode of administration, thespecific indication being treated and the judgment of the prescribingphysician. In cases of local administration or selective uptake, such aslocal topical administration, the effective local concentration ofactive compound(s) may not be related to plasma concentration. Skilledartisans will be able to optimize effective local dosages without undueexperimentation.

Preferably, the compound(s) will provide therapeutic or prophylacticbenefit without causing substantial toxicity. Toxicity of thecompound(s) may be determined using standard pharmaceutical procedures.The dose ratio between toxic and therapeutic (or prophylactic) effect isthe therapeutic index. Compounds(s) that exhibit high therapeuticindices are preferred.

The invention having been described, the following examples are offeredby way of illustration and not limitation.

7. EXAMPLES 7.1 Synthesis of Starting Materials and Intermediates Usefulfor Synthesizing the 2,4-Pyrimidinediamine Compounds According toSchemes (I)-(V)

A variety of starting materials andN4-monosubstituted-2-pyrimidineamines andN2-monosubstituted-4-pyrimidinediamines [mono Substitution NucleophilicAromatic Reaction (SNAR) products] useful for synthesizing the2,4-pyrimidinediamine compounds of the invention according to Schemes(I)-(V) were prepared as described below. Conditions suitable forsynthesizing the mono SNAR products are exemplified with2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine(R926087).

7.1.1 2,4-Dichloro-5-fluoropyrimidine

To a dry reaction flask equipped with a stir bar and a reflux condenserwas placed 5-fluorouracil (0.65 g, 5 mmol) followed by phosphorusoxychloride (POCl₃) (1.53 g, 10 mmol). The resultant mixture was heatedat 110° C. for 8 hours under a nitrogen atmosphere. The reaction wascooled to room temperature, phosphorus pentachloride (PCl₅) (3.12 g, 15mmol) was added and heated to 110° C. for a period of 12 hours. Aftercooling to room temperature, the mixture was poured into ice-water,saturated with sodium chloride and left for 1 hour at 0° C. to completethe decomposition of POCl₃ and PCl₅. The solid of2,4-dichloro-5-fluoropyrimidine was collected by rapid filtration, driedusing blotting paper and stored at low temperature. ¹H NMR (CDCl₃): δ8.47 (s, 1H); ¹³C NMR (CDCl₃): δ 155.42, 151.87, 147.43 and 147.13; ¹⁹FNMR (CDCl₃): −38149.

7.1.2 2,4-Dichloro-5-nitropyrimidine (Aldrich D6, 930-0)

A suspension of 5-nitrouracil (10 g, 63 mmol) in POCl₃ (100 mL) wasrefluxed for 5 h in the presence of N,N-dimethylaniline (10 mL), cooledto room temperature and poured on to crushed ice with vigorous stirring.The aqueous layer was extracted with ethyl acetate. The combined organiclayers were dried over MgSO₄ and the solvent was evaporated under reducepressure. The residue was purified by chromatography on silica gel(hexane/ethyl acetate; 1/1; v/v) to give the desired2,4-dichloro-5-nitropyrimidine. LCMS: ret. time: 23.26 min.; purity:95%; ¹H NMR (CDCl₃): δ 9.16 (1H, s).

7.1.3 2,4-Dichloro-5-cyanopyrimidine

In like manner to the preparation of 2,4-dichloro-5-nitropyrimidine, thereaction of 5-cyanouracil with POCl₃ and N,N-dimethylaniline gave2,4-dichloro-5-cyanopyrimidine. LCMS: ret. time: 13.75 min.; purity:95%.

7.1.4 2,4-Dichloro-5-trifluoromethylpyrimidine

In like manner to the preparation of 2,4-dichloro-5-nitropyrimidine, thereaction of 5-cyanouracil with POCl₃ and N,N-dimethylaniline gave2,4-dichloro-5-cyanopyrimidine. ¹H NMR (CD₃OD): δ 9.07; LCMS: ret. time:16.98 min. (fast method); purity: 70%.

7.1.5 2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine(R926087)

The reaction flask equipped with a magnetic stirring bar and a rubberseptum (to prevent loss of 2,4-dichloro-5-fluoropyrimidine and N₂ inletwas charged with 3,4-ethylenedioxyaniline (34 g, 225 mmol), MeOH (100mL), H₂O (300 mL) and 2,4-dichloro-5-fluoropyrimidine (25 g, 150 mmol).The reaction mixture was stirred at room temperature for 1 h, dilutedwith H₂O (1.5 liter), acidified with 2N HCl (200 mL) and sonicated. Thesolid obtained was filtered, washed with H₂O and dried to obtain 33 g(78%) of the desired product,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine(R926087). ¹H NMR (CDCl₃): δ 8.02 (1H, d, J=3 Hz), 7.25 (d, 1H, J=1.2Hz), 6.98 (dd, 1H, J=2.4 and 8.1 Hz), 6.85 (d, 1H, J=5.7 Hz), 4.27 (m,4H); ¹⁹F NMR (CDCl₃): −44570; LCMS: ret. time: 26.70 min.; purity 100%;MS (m/e): 283 (MH⁺).

7.1.6 2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-nitro-4-pyrimidineamine(R940094)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-nitropyrimidine and 3,4-ethylenedioxyaniline were reactedto prepare2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-nitro-4-pyrimidineamine. LCMS:ret. time: 28.79 min.; purity: 90%; MS (m/e): 308 (M⁺); ¹HNMR (CDCl₃): δ10.07 (1H, s), 9.15 (1H, s), 7.02-6.88 (3H, m), 4.29 (4H, s).

7.1.7 2-Chloro-N4-(3-hydroxyphenyl)-5-nitro-4-pyrimidineamine (R940097)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-nitropyrimidine and 3-hydroxyaniline were reacted toprepare 2-chloro-N4-(3-hydroxyphenyl)-5-nitro-4-pyrimidineamine. LCMS:ret. time: 24.21 min.; purity: 93%; MS (m/e): 267 (MH⁺); ¹HNMR (CDCl₃):δ 10.20 (1H, s), 9.19 (1H, s), 7.32 (1H, t, J=2.2 Hz), 7.28 (1H, d,J=7.8 Hz), 7.11 (1H, dd, J=7.8 and 1.8 Hz), 7.76 (1H, dd, J=8.4 and 2.4Hz), 5.20 (1H, s).

7.1.8 2-Chloro-N4-(3-hydroxyphenyl)-5-fluoro-4-pyrimidineamine (R926111)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 3-hydroxyaniline were reacted toprepare product2-chloro-N4-(3-hydroxyphenyl)-5-fluoro-4-pyrimidineamine. ¹H NMR(CD₃OD): δ 8.06 (bd, 1H), 7.26 (bd, 1H), 7.20-7.00 (m, 2H), 6.57 (d, 1H,J=7.2 Hz); ¹⁹F NMR (CD₃OD): −44374; LCMS: ret. time: 22.02; purity:100%, MS (m/e): 240 (M⁺).

7.1.9 2-Chloro-N4-(3,4-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine(R926073)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 3,4-dimethoxyaniline were reacted toprepare 2-chloro-N4-(3,4-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine. ¹HNMR (CDCl₃): δ 8.02 (d, 1H, J=2.7 Hz), 7.38 (d, 1H, J=2.4 Hz), 7.05 (dd,1H, J=2.4 and 9.0 Hz), 6.89 (bs, 1H), 6.88 (d, 1H, J=9 Hz), 3.91 (s,3H), 3.89 (s, 3H); ¹⁹F NMR (CDCl₃): −44593; LCMS: ret. time: 24.95 min.;purity: 98%; MS (m/e): 285 (MH⁺).

7.1.10 2-Chloro-N4-(4-ethoxyphenyl)-5-fluoro-4-pyrimidineamine (R926066)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-ethoxyaniline were reacted toprepare 2-chloro-N4-(4-ethoxyphenyl)-5-fluoro-4-pyrimidineamine. ¹H NMR(CDCl₃): δ 8.01 (d, 1H, J=3 Hz), 7.49 (bdd, 2H, J=8.7 Hz), 6.92 (bdd,2H, J=9.6 Hz), 4.03 (q, 2H, J=7.2 Hz), 1.42 (t, 3H, J=7.2 Hz); ¹⁹F NMR(CDCl₃): −44627; LCMS: ret. time: 29.50 min.; purity: 99%, MS (m/e): 268(MH⁺).

7.1.11 2-Chloro-N4-(4-chlorophenyl)-5-fluoro-4-pyrimidineamine (R926207)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-chloroaniline were reacted toprepare 2-chloro-N4-(4-chlorophenyl)-5-fluoro-4-pyrimidineamine. ¹H NMR(CDCl₃): δ 8.1 (bs, 1H), 8.60 (bdd, 2H), 8.36 (bdd, 2H), 6.90 (bs, 1H);¹⁹F NMR (CDCl₃): −44407; LCMS: ret. time: 31.63 min.; purity: 85%; MS(m/e): 258 (MH⁺).

7.1.122-Chloro-5-fluoro-N4-(3-hydroxy-4-methoxycarbonylmethyleneoxyphenyl)-4-pyrimidineamine(R926393)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and3-hydroxy-4-methoxycarbonylmethylenoxyaniline were reacted to prepare2-chloro-5-fluoro-N4-(3-hydroxy-4-methoxycarbonylmethyleneoxyphenyl)-4-pyrimidineamine.¹H NMR (CD₃OD): δ 8.03 (d, 1H, J=3.6 Hz), 7.35 (dd, 1H, J=2.4 Hz), 7.12(dd, 1H, J=2.4 and 8.7 Hz), 6.82 (d, 1H, J=8.1 Hz), 4.86 (s, 2H), 3.81(s, 3H).

7.1.13N4-(4-tert-Butoxycarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine(R926573)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and tert-butyl 4-aminophenoxyacetatewere reacted to prepare productN4-(4-tert-butoxycarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine.¹H NMR (CDCl₃): δ 8.02 (d, 1H, J=2.7 Hz), 7.51 (d, 1H, J=8.7 Hz), 6.93(d, 1H, J=8.7 Hz), 4.52 (s, 2H)), 1.49 (s, 9H); LCMS: ret. time: 29.50min.; purity: 97%; MS (m/e): 354 (MH⁺).

7.1.14 2-Chloro-5-fluoro-N4-(indol-5-yl)-4-pyrimidineamine (R926581)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 5-aminoindole were reacted toprepare 2-chloro-5-fluoro-N4-(indol-5-yl)-4-pyrimidineamine. ¹H NMR(CDCl₃+CD₃OD): δ 9.45 (bs, 1H), 8.00 (bs, 1H), 7.82 (bd, 1H), 7.75 (s,1H), 7.38-7.10 (m, 3H), 6.40 (bs, 1H); LCMS: ret. time: 23.85 min.;purity: 100%; MS (m/e): 263 (MH⁺).

7.1.152-Chloro-5-fluoro-N4-(4-methoxymethyl-coumarin-7-yl)-4-pyrimidineamine(R926618)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-methoxymethyl-7-aminocoumarin werereacted to prepare2-chloro-5-fluoro-N4-(4-methoxymethyl-coumarin-7-yl)-4-pyrimidineamine.¹H NMR (CD₃OD): δ 8.05 (d, 1H), 7.90 (s, 1H), 7.70 (dd, 1H, J=2.4 and8.7 Hz), 7.53 (d, 1H, J=8.7 Hz), 6.42 (s, 1H), 4.61 (s, 2H), 3.49 (s,3H); LCMS: ret. time: 26.38 min.; purity: 87%; MS (m/e): 336 (MH⁺).

7.1.162-Chloro-N4-(2,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine(R926619)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 2,5-dimethyl-4-hydroxyaniline werereacted to prepare2-chloro-N4-(2,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine.LCMS: ret. time: 23.31 min.; purity: 96%; MS (m/e): 268 (MH⁺).

7.1.17 2-Chloro-N4-(5-chloropyrid-2-yl)-5-fluoro-4-pyrimidineamine(R926061)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 5-chloro-2-aminopyridine werereacted to prepare2-chloro-N4-(5-chloropyrid-2-yl)-5-fluoro-4-pyrimidineamine. ¹H NMR(CDCl₃): δ 8.40 (d, 1H, J=8.7 Hz), 8.28 (d, 1H, J=1.8 Hz), 8.17 (d, 1H,J=2.1 and 9 Hz); LCMS: ret. time: 28.58 min.; purity: 100%; MS (m/e):259 (MH⁺).

7.1.18 2-Chloro-5-fluoro-N4-(5-methylpyrid-2-yl))-4-pyrimidineamine(R926062)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 5-methyl-2-aminopyridine werereacted to prepare2-chloro-5-fluoro-N4-(5-methylpyrid-2-yl)-5-4-pyrimidineamine. ¹H NMR(CDCl₃): δ 9.20 (s, 1H), 8.51 (s, 1H), 7.63 (d, 1H, J=5.7 Hz), 7.45 (dd,1H, J=1.8 and 9.3 Hz), 2.43 (s, 3H); LCMS: ret. time: 21.29 min.;purity: 97%; MS (m/e): 239 (MH⁺).

7.1.19 N4-[6-(1,4-Benzoxazinyl)]-N2-chloro-5-fluoro-4-pyrimidineamine

In like manner to2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 6-amino-1,4-benzoxazine were reacted(in methanol or methanol:water) to yieldN4-[6-(1,4-benzoxazinyl)]-N2-chloro-5-fluoro-4-pyrimidineamine. ¹H NMR(DMSO-d6): δ 8.2 (d, 1H), 6.8 (m, 1H), 6.75 (m, 1H), 6.60 (m, 1H), 4.05(m, 2H), 3.2 (m, 2H); LCMS: ret. time: 20.8 min.; purity: 95%; MS (m/e):295 (MH⁺).

7.1.20N2-Chloro-N4-(2,3-dihydrobenzofuran-5-yl)-5-fluoro-4-pyrimidinediamine

In like manner to2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 5-amino-2,3-dihydrobenzofuran werereacted to yieldN2-chloro-N4-(2,3-dihydrobenzofuran-5-yl)-5-fluoro-4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 8.09 (d, 1H), 8.00 (m, 1H), 7.42 (m, 2H), 7.05 (m,1H), 4.53 (m, 2H), 4.25 (s, 2H), 3.15 (m, 2H); LCMS: ret. time: 20.35min.; purity: 90%; MS (m/e): 266 (MH⁺).

7.1.21 2-Chloro-N4-(2-carboxy-4-chlorophenyl)-5-fluoro-4-pyrimidineamine(R940050)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 2-carboxy-4-chloroaniline werereacted to prepare2-chloro-N4-(2-carboxy-4-chlorophenyl)-5-fluoro-4-pyrimidineamine. LCMS:ret. time: 20.83 min.; purity: 98%; ¹H NMR (CDCl₃): δ 8.64 (1H, d, J=4.8Hz), 8.24 (1H, d, J=2.7 Hz), 7.76 (1H, dd, J=8.7 and 2.7 Hz), 7.70 (1H,dd, J=8.7 and J=0.9 Hz).

7.1.22 N-(2-Chloro-5-fluoro-4-pyrimidinyl)-L-tyrosine Methyl Ester(R940108)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and L-tyrosine methyl ester were reactedto prepare N-(2-chloro-5-fluoro-4-pyrimidinyl)-L-tyrosine Methyl Ester.LCMS: ret. time: 23.32 min.; purity: 83%; MS (m/e): 325 (M⁺); ¹H NMR(CDCl₃): δ 7.90 (1H, d, J=2.7 Hz), 6.95 (2H, d, J=8.7 Hz), 6.75 (2H, d,J=8.7 Hz), 5.95 (1H, s), 5.72 (1H, d, J=7.5 Hz), 5.05 (1H, dt, J=7.5 and5.3 Hz), 3.77 (3H, s), 3.16 (2H, m).

7.1.232-Chloro-N4-[3-(5-cyano-2-methyl-4-thiomethyl-6-pyrimidinyl)phenyl]-5-fluoro-4-pyrimidineamine(R940141)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and3-(5-cyano-2-methyl-4-thiomethyl-6-pyrimidinyl)aniline were reacted toprepare2-chloro-N4-[3-(5-cyano-2-methyl-4-thiomethyl-6-pyrimidinyl)phenyl]-5-fluoro-4-pyrimidineamine.LCMS: ret. time: 18.23 min.; purity: 84%; MS (m/e): 386 (M⁺); ¹H NMR(CDCl₃): δ 8.19 (1H, t, J=1.9 Hz), 8.11 (1H, d, J=3.1 Hz), 7.98 (1H, dd,J=8.1 and J=2.4 Hz), 7.82 (1H, dd, J=7.8 and 1.8 Hz), 7.57 (1H, t, J=7.8Hz), 7.11 (1H, s), 2.79 (3H, s), 2.69 (3H, s).

7.1.24N4-[4-(N-Benzylpiperazino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine(R945154)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,4-(N-benzylpiperazino)aniline and 2,4-dichloro-5-fluoropyrimidine gaveN4-[4-(N-benzylpiperazino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine.¹H NMR (CDCl₃): δ 2.81 (m, 4H), 3.37 (m, 6H), 6.85 (br, 1H), 6.93 (d,J=9.0 Hz, 2H), 7.40 (m, 5H), 7.50 (d, J=9.3 Hz, 2H), 8.02 (d, J=2.7 Hz,1H); LCMS: ret. time: 20.56 min, purity: 97.75%; MS (m/e): 398.00 (MH⁺).

7.1.252-Chloro-N4-(4-cyanomethyleneoxyphenyl)-5-fluoro-4-pyrimidineamine(R945069)

In a manner analogous to the preparation ofN2,N4-bis(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine,N4-(4-aminocarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine(178 mg, 0.6 mmol), trifluoroacetic anhydride (0.17 mL, 1.2 mmol) andpyridine (0.15 mL, 1.84 mmol) gave2-chloro-N4-(4-cyanomethyleneoxyphenyl)-5-fluoro-4-pyrimidineamine (110mg, 66%). ¹H NMR (acetone-d₆): δ 5.22 (s, 2H), 7.24 (d, J=9.3 Hz, 2H),7.62 (d, J=9.0 Hz, 2H), 8.94 (d, J=1.8 Hz, 1H); ¹⁹F NMR (acetone-d₆):−137.60; LCMS: ret. time: 26.19 min.; purity: 89.93%; MS (m/e): 279.06(MH⁺).

7.1.26 N4-(4-Acetoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine(R940210)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-acetoxyaniline were reacted toprepare N4-(4-acetoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine. LCMS:ret. time: 25.97 min.; purity: 98%; MS (m/e): 281 (M⁺); ¹H NMR (CDCl₃):δ 8.07 (1H, d, J=2.7 Hz), 7.64 (2H, d, J=9 Hz), 7.12 (2H, d, J=9 Hz),7.00 (1H, s), 2.31 (3H, s).

7.1.27 2-Chloro-5-fluoro-N4-(4-hydroxyphenyl)-4-pyrimidineamine(R940211)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-hydroxyaniline were reacted toprepare 2-chloro-5-fluoro-N4-(4-hydroxyphenyl)-4-pyrimidineamine. LCMS:ret. time: 20.10 min.; purity: 98%; MS (m/e): 240 (MH⁺); ¹H NMR (CDCl₃):δ 8.02 (1H, d, J=2.7 Hz), 7.46 (2H, d, J=8.7 Hz), 6.86 (2H, d, J=9 Hz),6.85 (1H, s), 4.94 (1H, s).

7.1.282-Chloro-N4-(2,3-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine(R940213)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 2,3-dimethyl-4-hydroxyaniline werereacted to prepare2-chloro-N4-(2,3-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine.LCMS: ret. time: 23.29 min.; purity: 93%; MS (m/e): 268 (MH⁺); ¹H NMR(CDCl₃): δ 8.00 (1H, d, J=2.7 Hz), 7.16 (1H, d, J=8.7 Hz), 6.68 (1H, d,J=8.7 Hz), 6.61 (1H, s), 4.87 (1H, s), 2.21 (3H, s), 2.16 (3H, s).

7.1.292-Chloro-N4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-4-pyrimidineamine(R940230)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-hydroxy-5-methylanilinewere reacted to prepare2-chloro-N4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-4-pyrimidineamine.LCMS: ret. time: 26.26 min.; purity: 90%; ¹H NMR (DMSO-d6): δ 9.94 (1H,s), 9.21 (1H, s), 8.37 (1H, d, 3.6 Hz), 7.68 (1H, s), 7.41 (1H, s), 2.30(3H, s).

7.1.302-Chloro-5-fluoro-N4-[4-[3-(N-morpholino)propyl]oxyphenyl]-4-pyrimidineamine(R940247)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-[3-(N-morpholino)propyl]oxyanilinewere reacted to prepare2-chloro-5-fluoro-N4-[4-[3-(N-morpholino)propyl]oxyphenyl]-4-pyrimidineamine.LCMS: ret. time: 17.15 min.; purity: 99%; MS (m/e): 367 (MH⁺); ¹H NMR(CDCl₃): δ 8.02 (1H, d, J=2.7 Hz), 7.49 (2H, d, J=8.7 Hz), 6.92 (2H, d,J=9 Hz), 6.85 (1H, s), 4.03 (2H, t, J=6.3 Hz), 3.73 (4H, t, J=4.6 Hz),2.53 (2H, t, J=6.7 Hz), 2.47 (4H, m), 1.98 (2H, m).

7.1.31N4-[2-[4-(N-Benzylpiperazino)ethyl]]-2-chloro-5-fluoro-4-pyrimidineamine(R940259)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine2,4-dichloro-5-fluoropyrimidine and 2-[4-(N-benzylpiperazino)ethylaminewere reacted to prepareN4-[2-[4-(N-benzylpiperazino)ethyl]]-2-chloro-5-fluoro-4-pyrimidineamine.LCMS: ret. time: 21.11 min.; purity: 96%; MS (m/e): 349 (M⁺); ¹H NMR(CDCl₃): δ 7.88 (1H, d, J=2.6 Hz), 7.31-7.17 (4H, m), 7.14 (1H, d, J=1.7Hz), 7.10 (1H, s), 3.76 (2H, m), 3.24 (2H, m), 2.90 (2H, m), 2.59 (2H,m), 2.34 (2H, m), 1.76 (4H, m).

7.1.32 N4-(3-tert-Butylphenyl)-2-chloro-5-fluoro-4-pyrimidineamine(R940268)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 3-tert-butylaniline were reacted toprepare N4-(3-tert-butylphenyl)-2-chloro-5-fluoro-4-pyrimidineamine.LCMS: ret. time: 33.96 min.; purity: 98%; MS (m/e): 279 (M⁺); ¹H NMR(CDCl₃): δ 8.05 (1H, d, J=3 Hz), 7.62 (1H, t, J=1.3 Hz), 7.50 (1H, m),7.34 (1H, t, J=7.8 Hz), 7.22 (1H, m), 6.96 (1H, sl), 1.34 (9H, s).

7.1.33 2-Chloro-5-fluoro-N4-[3-(hydroxymethyl)phenyl]-4-pyrimidineamine(R925756)

In a manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 3-aminobenzylalcohol were reacted toyield 2-chloro-5-fluoro-N4-[3-(hydroxymethyl)phenyl]-4-pyrimidineamine.¹H NMR (CDCl₃): δ 8.45 (bs, 1H), 7.96 (d, 1H, J=2.9 Hz), 7.65 (d, 1H,J=8.2 Hz), 7.34 (s, 1H), 7.31 (t, 1H, J=8.2 Hz), 7.07 (d, 1H, J=8.2),4.52 (s, 2H)); ¹⁹F NMR (CDCl₃): −44394 (s, 1F); LCMS: ret. time: 20.29min.; purity: 100%; MS (m/e): 254 (MH⁺).

7.1.34 2-Chloro-5-fluoro-N4-[4-(hydroxymethyl)phenyl]-4-pyrimidineamine(R925759)

In a manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-aminobenzylalcohol were reacted toyield 2-chloro-5-fluoro-N4-[4-(hydroxymethyl)phenyl]-4-pyrimidineamine.¹H NMR (CDCl₃): δ 8.08 (d, 1H, J=2.7 Hz), 7.62 (d, 2H, J=9.0 Hz), 7.40(d, 2H, J=8.1 Hz), 6.99 (bs, 1H), 4.70 (s, 2H); ¹⁹F NMR (CDCl₃): −44570(s, 1F); LCMS: ret. time: 19.57 min.; purity: 99%; MS (m/e): 254 (MH⁺).

7.1.352-Chloro-N4-(3,3-dihydroisobenzofuranynl-1-one-6-yl)-5-fluoro-4-pyrimidineamineR940279

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and6-amino-3,3-dihydroisobenzofuran-1-one were reacted to give2-chloro-N4-(3,3-dihydroisobenzofuranynl-1-one-6-yl)-5-fluoro-4-pyrimidineamine.LCMS: ret. time: 21.15 min.; purity: 94.7%; MS (m/e): 280 (MH⁺).

7.1.36 2-Chloro-5-fluoro-N4-((2R)-hydroxy-(1S)-methyl-2-phenylethyl)-4-pyrimidineamine (R925762)

In a manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and (1R,2S)-(−)-norephedrine werereacted to yield 2-chloro-5-fluoro-N4-(2R-hydroxy-1S-methyl-2-phenylethyl)-4-pyrimidineamine. ¹H NMR (CDCl₃): δ 7.85 (d,1H, J=3.0 Hz), 7.38 (m, 5H), 5.56 (d, 1H, J=7.5 Hz), 5.00 (d, 1H, J=3.0Hz), 4.54 (m, 1H), 2.87 (bs, 1H), 1.10 (d, 1H, J=6.9 Hz); ¹⁹F NMR(CDCl₃): −44408.

7.1.37 N-(2-Chloro-6-ethoxycarbonyl-5-nitro-4-pyrimidinyl)glycine EthylEster (R925850)

In a manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-6-ethoxycarbonyl-5-nitropyrimidine and glycine ethyl esterhydrochloride salt were reacted to yieldN-(2-chloro-6-ethoxycarbonyl-5-nitro-4-pyrimidinyl)glycine Ethyl Ester.¹H NMR (CDCl₃): δ 8.87 (bs, 1H), 4.48 (q, 2H, J=7.2 Hz), 4.39 (d, 2H,J=5.1 Hz), 1.40 (t, 3H, J=6.9 Hz), 1.33 (t, 3H, J=7.2 Hz); LCMS: ret.time: 28.27 min.; purity: 97%; MS (m/e): 332 (M⁺).

7.1.38 2-Chloro-5-fluoro-N4-(2-hydroxy-2-phenylethyl)-4-pyrimidineamine(R925763)

In a manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 2-amino-1-phenylethanol were reactedto yield2-chloro-5-fluoro-N4-(2-hydroxy-2-phenylethyl)-4-pyrimidineamine. ¹H NMR(CDCl₃): δ 7.88 (d, 1H, J=3.0 Hz), 7.41-7.32 (m, 5H), 5.71 (bs, 1H),4.97 (d, 1H, J=8.1 Hz), 3.98 (m, 1H), 3.56 (m, 1H), 2.57 (s, 1H); ¹⁹FNMR (CDCl₃): −45149; LCMS: ret. time: 22.27 min.; purity: 98%; MS (m/e):263 (M⁺).

7.1.39 2-Chloro-5-fluoro-N4-(furfuryl)-4-pyrimidineamine (R925764)

In a manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and furfurylamine were reacted to yield2-chloro-5-fluoro-N4-(furfuryl)-4-pyrimidineamine. ¹H NMR (CDCl₃): δ7.91 (d, 1H, J=1.8 Hz), 7.39 (d, 1H, J=1.2 Hz), 6.35 (m, 2H), 5.50 (bs,1H), 4.69 (d, 2H, J=5.1 Hz); ¹⁹F NMR (CDCl₃): −45163; LCMS: ret. time:24.52 min.; purity: 97%; MS (m/e): 228 (M⁺).

7.1.40 R935010:(+)-2-Chloro-5-fluoro-N4-[1-(4-hydroxyphenyl)ethyl]-4-pyrimidineamine

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine was reacted with1-(4-hydroxyphenyl)ethylamine to provide(+)-2-chloro-5-fluoro-N4-[1-(4-hydroxyphenyl)ethyl]-4-pyrimidineamine.¹H NMR (CDCl₃): δ 7.88 (d, 1H, J=2.3 Hz), 7.50-7.47 (dd, 2H, J=1.7 and8.7 Hz), 7.26-7.23 (dd, J=8.7 and 1.7 Hz), 5.35-5.28 (m, 2H), 1.59 (d,3H, J=7.0 Hz).

7.1.41 R935011:(+)-N4-[1-(4-Bromophenyl)ethyl]-2-chloro-5-fluoro-4-pyrimidineamine

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine was reacted with1-(4-bromophenyl)ethylamine to provide(+)-N4-[1-(4-bromophenyl)ethyl]-2-chloro-5-fluoro-4-pyrimidineamine: ¹HNMR (CDCl₃): δ 7.88 (d, 1H, J=2.3 Hz), 7.49 (d, 2H, J=8.7 Hz), 7.25 (d,2H, J=8.7 Hz), 4.45-5.26 (m, 2H), 1.59 (d, 3H, J=7.0 Hz).

7.1.42 R935007:2-chloro-5-fluoro-N4-[1-[(1S)-phenyl]ethyl]-4-pyrimidineamine

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 1-(1S)-phenyl ethylamine werereacted to produce2-chloro-5-fluoro-N4-[1-[(1S)-phenyl]ethyl]-4-pyrimidineamine. ¹H NMR(CDCl₃): δ 7.86 (d, 1H, J=2.9 Hz), 7.37 (d, 4H, J=4.7 Hz), 7.34-7.30 (m,1H), 5.40-5.32 (m, 2H), 1.62 (d, 3H, J=6.4 Hz); LCMS: ret. time: 29.5min.; purity: 98%; MS (m/e): 252 (MH⁺).

7.1.43 R935008:2-Chloro-5-fluoro-N4-[1-[(1R)-pheny]ethyl]-4-pyrimidineamine

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 1-(1R)-phenyl ethylamine werereacted to produce2-chloro-5-fluoro-N4-[1-[(1R)-phenyl]ethyl]-4-pyrimidineamine. ¹H NMR(CDCl₃): δ 7.87 (d, 1H, J=2.9 Hz), 7.37 (d, 4H, J=4.1 Hz), 7.34-7.30 (m,1H), 5.38-5.31 (m, 2H), 1.62 (d, 3H, J=6.4 Hz).

7.1.44 R935012:2-Chloro-N4-[[di(3,5-di(trifluoromethyl)phenyl)]methyl]-5-fluoro-4-pyrimidineamine

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine was reacted withdi[3,5-di(trifluoromethyl)phenyl]methylamine to provide2-chloro-N4-[[di(3,5-di(trifluoromethyl)phenyl)]methyl]-5-fluoro-4-pyrimidineamine.¹H NMR (CDCl₃): δ 8.06 (d, 1H, J=2.3 Hz), 7.92 (s, 2H), 7.74 (s, 4H),6.75 (d, 1H, J=7.6 Hz), 5.80 (d, 1H, J=7.0 Hz).

7.1.45 R935014:2-Chloro-5-fluoro-N4-[1-[(1R)-4-methoxyphenyl]ethyl]-4-pyrimidineamine

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine was reacted with(R)-(+)-1-(4-methoxyphenyl)ethylamine to provide2-chloro-5-fluoro-N4-[1-[(1R)-4-methoxyphenyl]ethyl]-4-pyrimidineamine.¹H NMR (CDCl₃): δ 7.84 (d, 1H, J=2.3 Hz), 7.30 (d, 2H, J=8.8 Hz), 6.89(d, 2H, J=8.8 Hz), 5.39-5.26 (m, 2H), 3.80 (s, 3H), 1.59 (d, 3H, J=6.4Hz).

7.1.46 R935015:2-Chloro-5-fluoro-N4-[1-[(1S)-4-methoxyphenyl]ethyl]-4-pyrimidineamine

In like manner to the preparation of2-chloro-5-fluoro-N4-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine was reacted with(S)-(−)-1-(4-methoxyphenyl)ethylamine to provide2-chloro-5-fluoro-N4-[1-[(1S)-4-methoxyphenyl]ethyl]-4-pyrimidineamine.¹H NMR (CDCl₃): δ 7.85 (d, 1H, J=2.3 Hz), 7.31 (d, 2H, J=8.8 Hz), 6.89(d, 2H, J=8.8 Hz), 5.38-5.29 (m, 2H), 3.80 (s, 3H), 1.59 (d, 3H, J=7.7Hz).

7.1.47 R935013: 2-Chloro-N-(fluoren-9-yl)-5-fluoro-4-pyrimidineamine

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro 4-pyrimidineamine,9-aminofluorene hydrochloride and 2,4-dichloro-5-fluoropyrimidine withadded diisopropylethylamine were reacted to produce2-chloro-N-(fluoren-9-yl)-5-fluoro-4-pyrimidineamine. ¹H NMR (CDCl₃): δ7.97 (d, 1H, J=2.3 Hz), 7.73 (d, 2H, J=7.6 Hz), 7.59 (d, 2H, J=7.6 Hz),7.44 (t, 2H, J=7.6 Hz), 7.32 (app t, 2H, J=7.6 Hz), 6.50 (d, 1H, J=8.8Hz), 5.45 (d, 1H, J=8.4 Hz).

7.1.48 R935210:2-Chloro-5-fluoro-N-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-4-pyrimidineamine

In like manner to the preparation of2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,experiment, 2,4-dichloro-5-fluoropyrimidine was reacted with4-(methoxycarbonylmethyleneoxy)aniline to produce2-chloro-5-fluoro-N-[4-(methoxycarbonylmethyleneoxy)phenyl]-4-pyrimidineamine.¹H NMR (DMSO-d6): δ 10.17 (s, 1H), 8.33 (d, 1H, J=3.5 Hz), 8.05 (s, 1H),7.91 (s, 1H), 7.74 (d, 1H, J=8.2 Hz), 7.40 (d, 1H, J=7.6 Hz), 5.31 (s,2H), 3.66 (s, 3H).

7.1.49 R935200:2-Chloro-5-fluoro-N-(1-methyl-indazoline-5-yl)-4-pyrimidineamine

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 5-amino-1-methyl-indazoline werereacted to provide2-chloro-5-fluoro-N-(1-methyl-indazoline-5-yl)-4-pyrimidineamine. ¹H NMR(DMSO-d6): δ 10.01 (s, 1H), 8.27 (d, 1H, J=3.5 Hz), 8.04 (d, 1H, J=1.7Hz), 7.98 (d, 1H, J=1.7 Hz), 7.64 (d, 1H, J=8.8 Hz), 7.56 (dd, 1H, J=1.7and 8.8 Hz), 4.02 (s, 3H). LCMS: ret. time: 21.72 min.; purity: 99%; MS(m/e): 278 (MH⁺).

7.1.50 R935017: N-(5-Bromo-2-chloropyrimidinyl)-4-fluorophenylethylamine

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro 4-pyrimidineamine,4-fluoro-α-methylbenzylamine and 5-bromo-2,4-dichloropyrimidine werereacted to produceN-(5-bromo-2-chloropyrimidinyl)-4-fluorophenylethylamine. ¹H NMR(CDCl₃): δ 8.12 (s, 1H), 7.35-7.25 (dd, 2H, J=3.5 and 8.7 Hz), 7.05 (t,1H, J=8.7 Hz), 5.63 (d, 1H, J=6.4 Hz), 5.36 (dq, 1H, 1H, J=6.4 and 7.0Hz), 1.60 (d, 3H, J=7.0 Hz); LCMS: ret. time: 30.73 min.; purity: 94%;MS (m/e): 331 (MH⁺).

7.1.51 R935009:(+)-N-(2-Chloro-5-fluoropyrimidinyl)-1-(4-fluorophenyl)ethylamine

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro 4-pyrimidineamine,4-fluoro-α-methylbenzylamine and 2,4-dichloro-5-fluoropyrimidine werereacted to produce(+)-N-(2-chloro-5-fluoropyrimidinyl)-1-(4-fluorophenyl)ethylamine. ¹HNMR (CDCl₃): δ 7.87 (d, 1H, J=2.3 Hz), 7.37-7.33 (dd, 2H, J=5.4 and 8.4Hz), 7.04 (t, 2H, J=8.4 Hz), 5.35-5.31 (m, 2H), 1.60 (d, 3H, J=6.4 Hz);LCMS: ret. time: 32.90 min.; purity: 98%; MS (m/e): 270 (MH⁺).

7.1.52 R935022:5-Bromo-2-chloro-N4-[4-(N-methyl-2-methoxycarbonyl)ypyrrolyl)-4-pyrimidineamine

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro 4-pyrimidineamine,5-bromo-2,4-dichloropyrimidine andN-methyl-2-carbomethoxy-4-aminopyrrole hydrochloride with addeddiisopropylethylamine were reacted to produce the desired product5-bromo-2-chloro-N—(N-methyl-2-carbomethoxypyrrol-4-yl)-4-pyrimidineamine.¹H NMR (CDCl₃): δ 8.21 (s, 1H), 7.43 (d, 1H, J=1.8 Hz), 7.13 (br s, 1H),6.84 (d, 1H, J=1.8 Hz), 3.95 (s, 3H), 3.82 (s, 3H); LCMS: ret. time:26.96 min.; purity: 91%; MS (m/e): 346 (MH⁺).

7.1.53 R935234:2-Chloro-5-fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamine

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and5-(4-aminophenoxymethyl)-3-phenyl-1,2-4-oxadiazole were reacted toproduce2-chloro-5-fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamine.¹H NMR (DMSO-d₆): δ 9.92 (s, 1H), 8.26 (d, 1H, J=3.5 Hz), 8.02-7.99 (m,2H), 7.60-7.56 (m, 5H), 7.11 (d, 2H, J=8.8 Hz), 5.58 (s, 2H); LCMS: ret.time: 32.09 min.; purity: 96%; MS (m/e): 398 (MH⁺).

7.1.54 R935235:2-Chloro-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamine

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and5-(4-aminophenoxymethyl)-3-methyl-1,2-4-oxadiazole were reacted toproduce2-chloro-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamine.¹H NMR (DMSO-d₆): δ 9.91 (s, 1H), 8.26 (d, 1H, J=3.5 Hz), 7.56 (d, 2H,J=8.8 Hz), 7.05 (d, 2H, J=8.8 Hz), 5.46 (s, 2H), 2.34 (s, 3H); LCMS:ret. time: 25.05 min.; purity: 98%; MS (m/e): 336 (MH⁺).

7.1.55 R935236:2-Chloro-5-fluoro-N4-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-4-pyrimidineamine

In like manner to the preparation of2-chloro-N4-(3,4-ethyleneioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and4-[1-ethoxycarbonyl-1-methyl)ethyl]aniline were reacted to produce2-chloro-5-fluoro-N4-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-4-pyrimidineamine.¹H NMR (DMSO-d₆): δ 9.99 (s, 1H), 8.30 (d, 1H, J=3.5 Hz), 7.60 (d, 2H,J=8.8 Hz), 7.30 (d, 2H, J=8.8 Hz), 4.04 (qt, 2H, J=7.0 Hz), 1.47 (s,6H), 1.10 (t, 3H, J=7.0 Hz); LCMS: ret. time: 31.07 min.; purity: 97%;MS (m/e): 338 (MH⁺).

7.1.56 2,4-Dichloro-5-ethoxycarbonylpyrimidine

A dry reaction flask equipped with a stirring bar and a reflux condenserwas charged with 5-ethoxycarbonyluracil (1.84 g, 10 mmol), POCl₃ (10 mL)and N,N-dimethylaniline (1 mL) and heated at 90° C. for 2 h. The excessPOCl₃ was removed under a reduced pressure and quenched with ice-water(100 g). The aqueous solution was extracted with ethyl ether (3×100 mL),washed with saturated aqueous NaHCO₃ solution and water (100 mL, each).After drying over sodium sulfate, the ethyl ether was removed and theresidue was dried under a high vacuum to afford2,4-dichloro-5-ethoxycarbonylpyrimidine. H NMR (CDCl₃): δ 9.00 (s, 1H),4.45 (q, 2H, J=6.9 Hz), 1.42 (t, 3H, J=6.9 Hz).

7.1.57 N-(2-Chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-phenylalanine EthylEster (R926518) andN-(4-Chloro-5-ethoxycarbonyl-2-pyrimidinyl)-L-phenylalanine Ethyl Ester(R926519)

A mixture of L-phenylalanine Ethyl Ester Hydrochloride (0.137 g, 0.6mmol) 2,4-dichloro5-ethoxycarbonylpyrimidine (0.112 g, 0.5 mmol),triethylamine (0.7 mL, 0.6 mmol) in THF (4 mL) in a sealed tube washeated at 100° C. for 3 h. The reaction was diluted with H₂O (20 ML),extracted with CH₂Cl₂ (3×50 mL), washed with 2N HCl (10 mL), water (10mL) and solvent was evaporated. The residue obtained was purified bypreparative TLC using 15% EtOAc in hexanes to obtain two productsmainly, N-(2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-phenylalanineEthyl Ester (R926518). ¹H NMR (CDCl₃): δ 8.72 (d, 1H, J=6.92 Hz), 8.66(s, 1H), 7.32-7.17 (m, 5H), 5.05 (dq, 1H, J=1.2 and 5.7 Hz), 4.34 (q,2H, J=6.9 Hz), 4.20 (q, 2H, J=5.1 Hz), 3.24 (dd, 1H, J=5.4 Hz), 3.16(dd, 1H, J=7.5 Hz), 1.35 (t, 3H, J=7.2 Hz), 1.24 (t, 3H, J=7.2 Hz);LCMS: ret. time: 37.15 min.; purity: 99%; MS (m/e): 378 (MH⁺) andN-(4-chloro-5-ethoxycarbonyl-2-pyrimidinyl)-L-phenylalanine Ethyl Ester(R926519). ¹H NMR (CDCl₃): δ 8.83 (s, 1H), 7.28 (m, 3H), 7.18 (m, 2H),6.00 (bt, 1H), 4.99 (bdq, 1H), 4.36 (q, 2H, J=7.8 Hz), 4.19 (q, 2H,J=6.9 Hz), 3.20 (t, 2H, J=6.9 Hz). 1.38 (t, 3H, J=4.5 Hz), 1.24 (t, 3H,J=6 Hz); LCMS: ret. time: 34.80 min.; purity: 88%; MS (m/e): 378 (M⁺).

7.1.58 N-(2-Chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-valine Ethyl Ester(R926520) and N-(4-Chloro-5-ethoxycarbonyl-2-pyrimidinyl)-L-valine EthylEster (R926521)

In like manner to the preparation ofN-(2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-phenylalanine Ethyl Ester,2,4-dichloro-5-ethoxycarbonylpyrimidine and L-valine Ethyl Ester werereacted to prepare N-(2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-valineEthyl Ester (R926520). ¹H NMR (CDCl₃): δ 8.80 (d, 1H, J=8.1 Hz), 8.68(s, 1H), 4.77 (dd, 1H, J=4.8 Hz), 4.36 (q, 2H, J=7.2 Hz), 4.24 (q, 2H,J=6.6 Hz), 2.38 (m, 1H), 1.39 (t, 3H, J=6.9 Hz), 1.29 (t, 3H, J=7.2 Hz),1.03 (d, 3H, J=3 Hz), 1.00 (d, 3H, J=2.7 Hz); LCMS: ret. time: 36.54min.; purity: 89%; MS (m/e): 330 (MH⁺) andN-(4-chloro-5-ethoxycarbonyl-2-pyrimidinyl)-L-valine Ethyl Ester(R926521). ¹H NMR (CDCl₃): δ 8.82 (s, 1H), 6.02 (m, 1H), 4.69 (dd, 1H,J=4.8 and 4.5 Hz), 4.33 (q, 2H, J=7.5 Hz), 4.23 (q, 2H, J=7.5 Hz), 2.28(sept, 1H). 1.34 (t, 3H, J=6.9 Hz), 1.28 (t, 3H, J=7 Hz), 1.00 (d, 6H,J=7.2 Hz); LCMS: ret. time: 33.53 min.; purity: 91%; MS (m/e): 330 (M⁺).

7.1.59 N-(2-Chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-leucine Ethyl Ester(R926522)

In like manner to the preparation ofN-(2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-phenylalanine Ethyl Ester,2,4-dichloro-5-ethoxycarbonylpyrimidine and L-leucine Ethyl Ester werereacted to prepare N-(2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-leucineEthyl Ester. ¹H NMR (CDCl₃): δ 8.69 (s, 1H), 8.64 (d, 1H, 7.8 Hz), 4.84(s, 1H), 4.38 (q, 2H, J=7.2 Hz), 3.75 (s, 3H), 1.73 (m, 2H), 1.39 (t,3H, J=6.9 Hz), 0.97 (d, 3H, J=4.2 Hz), 0.95 (d, 3H, J=4.8 Hz); LCMS:ret. time: 36.09 min.; purity: 92%; MS (m/e): 330 (MH⁺).

7.1.60 N-(2-Chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-alanine Ethyl Ester(R926523) and N-(4-Chloro-5-ethoxycarbonyl-2-pyrimidinyl)-L-alanineEthyl Ester (R926524)

In like manner to the preparation ofN-(2-chloro-ethoxycarbonyl-4-pyrimidinyl)-L-phenylalanine Ethyl Ester,2,4-dichloro-5-ethoxycarbonylpyrimidine and L-valine Ethyl Ester werereacted to prepare N-(2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-alanineEthyl Ester (R926523). ¹H NMR (CDCl₃): δ 8.80 (bd, 1H), 8.68 (s, 1H),4.79 (q, 1H, J=7.2 Hz), 4.35 (q, 2H, J=7.2 Hz), 4.24 (m, 2H), 1.53 (d,3H, J=7.2 Hz), 1.38 (t, 3H, J=7.2 Hz), 1.29 (t, 3H, J=7.2 Hz); LCMS:ret. time: 31.89 min.; purity: 94%; MS (m/e): 303 (MH⁺) andN-(4-chloro-5-ethoxycarbonyl-2-pyrimidinyl)-L-alanine Ethyl Ester(R926524). ¹H NMR (CDCl₃): δ 8.80 (s, 1H), 6.01 (bs, 1H), 4.65 (bq, 1H),4.35 (q, 2H), 4.20 (q, 2H), 1.55, t, 3H), 1.40 (t, 3H), 1.25 (t, 3H);LCMS: ret. time: 28.78 min.; purity: 84%; MS (m/e): 302 (M⁺).

7.1.61 2-Chloro-N4-(4-n-butyloxyphenyl)-5-fluoro-4-pyrimidineamine

To a solution of 2,4-dichloro-5-fluoropyrimidine (0.5 g, 3.0 mmol) and4-n-butoxyaniline (0.49 g, 3 mmol) in acetone/H₂O (1:9 mL) at roomtemperature was added concentrated HCl (0.1 mL). The mixture was heatedat reflux for 1 h, cooled to room temperature, and made basic with 2 NNaOH (2 mL). The aqueous layer was extracted with EtOAc (2×50 mL) andthe combined organic extracts were dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude black solid was purified bychromatography (4:1 hexanes/EtOAc) to afford2-chloro-N4-(4-n-butyloxyphenyl)-5-fluoro-4-pyrimidineamine (0.71 g,80%) as a brown oil: ¹H NMR (300 MHz, CDCl₃) δ 8.01 (d, J=2.7 Hz, 1H),7.51-7.46 (m, 2H), 6.95-6.89 (m, 2H), 6.83 (bs, 1H), 3.99-3.95 (t, J=6.5Hz, 2H), 1.82-1.57 (m, 2H), 1.53-1.43 (m, 2H), 0.98 (t, J=7.2 Hz, 3H).

7.1.62 2-Chloro-N4-(4-n-hexyloxyphenyl)-5-fluoro-4-pyridineamine

In like manner to the preparation of2-chloro-N4-(4-n-butyloxyphenyl)-5-fluoro-4-pyrimidineamine, thereaction of 2,4-dichloro-5-fluoropyrimidine with 4-n-hexyloxyanilinegave 2-chloro-N4-(4-n-hexyloxyphenyl)-5-fluoro-4-pyridineamine. Thecrude product was purified by chromatography (4:1 CHCl₃/EtOAc) to afford(14) (0.74 g, 76%) as a red-brown oil that solidified upon standing: ¹HNMR (300 MHz, CDCl₃) δ 8.01 (d, J=2.7 Hz, 1H), 7.50 (d, J=9.0 Hz, 2H),6.92 (d, J=9.0 Hz, 2H), 6.84 (bs, 1H), 3.96 (t, J=6.5 Hz, 2H), 1.83-1.74(m, 2H), 1.48-1.41 (m, 2H), 1.36-1.34 (m, 4H), 0.93-0.89 (m, 3H).

7.1.63 N4-(3-Benzyloxyphenyl)-2-chloro-4-pyrimidineamine

A mixture of 2,6-dichloropyrimidine (2.00 g, 13.4 mmol),3-benzyloxoaniline (2.07 g, 13.4 mmol) and triethylamine (2.72 g, 26.8mmol) in 1-butanol (20 mL) was stirred at 50° C. for 17 h. The reactionmixture was concentrated to remove most of the 1-butanol, the crudeproduct was preadsorbed onto silica gel using chloroform and purified byflash chromatography (95:5 chloroform/methanol) to affordN4-(3-benzyloxyphenyl)-2-chloro-4-pyrimidineamine (1.70 g, 40%) ascolorless oil: ¹H NMR (300 MHz, DMSO-d₆) δ 10.2 (s, 1H), 8.16 (d, J=6.0Hz, 1H), 7.48-7.24 (m, 7H), 7.12 (d, J=9.0 Hz, 1H), 6.78 (m, 2H), 5.11(s, 2H); ESI MS m/z 312 [C₁₇H₁₄ClN₃O+H]⁺.

7.1.64N4-[4-(tert-Butoxycarbonylmethyleneoxy)phenyl]-3-chloro-5-ethoxycarbonyl-4-pyrimidineamine(R926578)

In like manner to the preparation ofN-(2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-phenylalanine Ethyl Ester,5-carboxyethoxy-2,4-dichloropyrimidine and tert-butyl4-aminophenoxyacetatewere reacted to prepareN4-[4-(tert-butoxycarbonylmethyleneoxy)phenyl]-2-chloro-5-ethoxycarbonyl-2-chloro-4-pyrimidineamine.LCMS: MS (m/e): 407 (MH⁺).

7.1.65N4-(4-Ethoxyphenyl)-5-ethoxycarbonyl-2-trifluoromethyl-4-pyrimidineamine(R926059)

In like manner to the preparation ofN-(2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-phenylalanine Ethyl Ester,4-chloro-5-ethoxycarbonyl-2-trifluoromethylpyrimidine and4-ethoxyaniline were reacted to prepareN4-(4-ethoxyphenyl)-5-ethoxycarbonyl-2-trifluoromethyl-4-pyrimidineamine.¹H NMR (CDCl₃): δ 10.39 (s, 1H), 9.02 (s, 1H), 7.59 (dd, 2H, J=2.1 and7.2 Hz), 6.91 (dd, 2H, J=1.8 and 6.6 Hz), 4.44 (q, 2H, J=7.5 Hz), 4.06(q, 2H, J=7.2 Hz), 1.44 (m, 6H); LCMS: ret. time: 38.49 min.; purity:100%; MS (m/e): 356 (MH⁺).

7.1.66N2-(4-Ethoxyphenyl)-5-methoxycarbonyl-4-trifluoromethyl-2-pyrimidineamine(R926060)

In like manner to the preparation ofN-(2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-phenylalanine Ethyl Ester,2-chloro-5-methoxycarbonyl-4-trifluoromethylpyrimidine and4-ethoxyaniline were reacted to prepareN2-(2-ethoxyphenyl)-5-methoxycarbonyl-4-trifluoromethyl-2-pyrimidineamine.¹H NMR (CDCl₃): δ 8.98 (s, 1H), 7.47 (m, 3H), 6.91 (dd, 2H, J=2.1 and6.9 Hz), 4.05 (q, 2H, 6.9 Hz), 1.42 (t, 3H, J=6.8 Hz); ¹⁹F NMR (CDCl₃):−19105; LCMS: ret. time: 33.87 min; purity: 100%; MS (m/e): 342 (MH⁺).

7.1.672-Chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine(R926853)

A reaction mixture containing 2,4-dichloro-5-fluoro-pyrimindine (1.2equivalents) and 3-(tetrazol-5-yl)aniline (1 equivalents) inmethanol:water (1:1; v/v) was heated at 60° C. for 24 h. Upon dilutionwith water and acidification, the solid formed was filtered, washed withwater, dried and analyzed to give2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine(R926853). Alternatively this reaction can be achieved by treating2,4-dichloro-5-fluoropyrimidine (1 equivalent) with3-(tetrazol-5-yl)aniline (3 equivalents) in methanol:water (1:1; v/v) at60° C. for 2-3 hours or at room temperature for 24 h to give2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine. ¹HNMR (DMSO-d6): δ 10.25 (s, 1H), 8.43 (s, 1H), 8.37 (d, 1H, J=3.6 Hz),7.90 (dd, 1H, J=0.9 and 9 Hz), 7.75 (d, 1H, J=7.5 Hz), 7.61 (t, 1H,J=7.8 Hz); LCMS: purity: 90%; MS (m/e): 292 (MH⁺).

7.1.682-Chloro-N4-(2,5-dimethoxy-4-chlorophenyl)-5-fluoro-4-pyrimidineamine(R926858)

In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with2,5-dimethoxy-4-chloroaniline gave2-chloro-N4-(2,5-dimethoxy-4-chlorophenyl)-5-fluoro-4-pyrimidineamine.LCMS: purity: 97%; MS (m/e): 316 (M-2H) and 320 (M+2H).

7.1.692-Chloro-5-fluoro-N4-(3-methoxycarbonyl-5-trifluoromethylphenyl)-4-pyrimidineamine(R926861)

In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with3-methoxycarbonyl-5-trifluoromethylaniline gave2-chloro-5-fluoro-N4-(3-methoxycarbonyl-5-trifluoromethylphenyl)-4-pyrimidineamine.¹H NMR (CD₃OD): δ 8.60 (s, 1H), 8.43 (s, 1H), 8.20 (d, 1H, J=3 Hz), 7.99(s, 1H), 3.96 (s, 3H); ¹⁹F NMR (CD₃OD): −18332,−18374; and −44259; LCMS:purity: 91%; MS (m/e): 350 (MH⁺).

7.1.702-Chloro-5-fluoro-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl)-4-pyrimidineamine(R926869)

In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with3-(2-phenyl-1,3,4-oxadiazol-5-yl)aniline gave2-chloro-5-fluoro-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl)-4-pyrimidineamine.¹H NMR (DMSO-d6): δ 10.28 (s, 1H), 8.62 (s, 1H), 8.39 (d, 1H, J=3.3 Hz),8.11 (m, 2H), 7.98 (bd, 1H, J=6.9 Hz), 7.88 (bd, 1H, J=8.4 Hz), 7.65 (m,4H); LCMS: purity: 76%; MS (m/e): 76%.

7.1.712-Chloro-N4-[3-(2-ethoxycarbonylmethylene-1,3,4-oxadiazol-5-yl)phenyl)-5-fluoro-4-pyrimidineamine(R926873)

In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with3-(2-ethoxycarbonylmethylene-1,3,4-oxadiazol-5-yl)aniline gave2-chloro-N4-[3-(2-ethoxycarbonylmethylene-1,3,4-oxadiazol-5-yl)phenyl]-5-fluoro-4-pyrimidineamine.¹H NMR (CD₃OD): δ 8.42 (t, 1H, J=1.8 Hz), 8.19 (d, 1H, J=3.3 Hz), 7.99(dt, 1H, J=1.2 and 8.1 Hz), 7.82 (dt, 1H, J=1.2 and 8.1 Hz), 7.58 (t,1H, J=9 Hz), 4.24 (q, 2H, J=3.9 Hz), 4.17 (s, 2H), 1.28 (t, 3H, J=7.2Hz); LCMS: purity: 85%; MS (m/e): 379 (MH⁺).

7.1.72 2-Chloro-5-fluoro-N4-(4-trifluoromethoxyphenyl)-4-pyrimidineamine(R926875)

In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with4-trifluoromethoxyaniline gave2-chloro-5-fluoro-N4-(4-trifluoromethoxyphenyl)-4-pyrimidineamine. ¹HNMR (CDCl₃): δ 8.11 (d, 1H, J=2.1 Hz), 7.68 (dd, 2H, J=2.4 and 7.6 Hz),7.26 (dd, 2H, J=3 and 8.7 Hz), 7.0 (bs, 1H); ¹⁹F NMR (CD₃OD): δ −16517and −44523; LCMS: purity: 94%; MS (m/e): 308 (MH⁺).

7.1.73 2-Chloro-5-fluoro-N4-(4-trifluoromethylphenyl)-4-pyrimidineamine(R926876)

In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with4-trifluoromethylaniline gave2-chloro-5-fluoro-N4-(4-trifluoromethylphenyl)-4-pyrimidineamine. ¹H NMR(CDCl₃): δ 8.15 (d, 2.1 Hz), 7.80 (d, 2H, J=7.1 Hz), 7.66 (d, 2H, J=9Hz), 7.10 (bs, 1H); ¹⁹F NMR (CDCl₃): −17682 and −44362; LCMS: purity:91% and MS (m/z): 292 (MH⁺).

7.1.742-Chloro-N4-(4-chloro-3-trifluoromethylphenyl)-5-fluoro-4-pyrimidineamine(R926877)

In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with4-chloro-3-trifluoromethylaniline gave2-chloro-N4-(4-chloro-3-trifluoromethylphenyl)-5-fluoro-4-pyrimidineamine.¹H NMR (CDCl₃): δ 8.15 (d, 1H, J=2.1 Hz), 7.96 (d, 1H, J=3 Hz), 7.91(dd, 1H, J=2.7 Hz and 8.7 Hz), 7.53 (d, 1H, J=8.1 Hz), 7.06 (bs, 1H);¹⁹F NMR (CDCl₃): −17892 and −44402; LCMS: purity: 93%; MS (m/e): 326(M⁺).

7.1.75 2-Chloro-5-fluoro-N4-(6-methoxypyridin-3-yl)-4-pyrimidineamine(R926878)

In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with3-amino-6-methoxypyridine gave2-chloro-5-fluoro-N4-(6-methoxypyridin-3-yl)-4-pyrimidineamine. ¹H NMR(CD₃OD): δ 8.39 (d, 1H, J=3.0 Hz), 8.10 (d, 1H, J=3.6 Hz), 7.95 (dd, 1H,J=2.4 and 9 Hz), 8.30 (d, 1H, J=9 Hz), 3.91 (s, 3H); ¹⁹F NMR (CD₃OD):−44737; LCMS: purity: 97%; MS (m/e): 255 (M⁺).

7.1.76 2-Chloro-N4-(3,4-difluorophenyl)-5-fluoro-4-pyrimidineamine(R926882)

In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with 3,4-difluoroanilinegave 2-chloro-N4-(3,4-difluorophenyl)-5-fluoro-4-pyrimidineamine. ¹H NMR(CDCl₃): δ 8.10 (d, 1H, J=2.1 Hz), 7.72 (m, 1H), 7.22 (m, 2H), 6.95 (bs,1H); LCMS: purity: 93%; MS (m/e): 260 (M⁺).

7.1.77 2-Chloro-N4-(3,4-Dichlorophenyl)-5-fluoro-4-pyrimidineamine(R926884)

In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with 3,4-dichloroanilinegave 2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine. LCMS:purity: 95%; MS (m/e): 294 (M+2H).

7.1.78 2-Chloro-5-fluoro-N4-(6-methylpyridin-2-yl)-4-pyrimidineamine(R926888)

In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with2-amino-6-methylpyridine gave2-chloro-5-fluoro-N4-(6-methylpyridin-2-yl)-4-pyrimidineamine. ¹H NMR(CDCl₃): δ 8.23 (s, 1H), 8.19 (s, 1H), 8.12 (d, 1H, J=3 Hz), 7.55 (bs,1H), 7.69 (t, 1H, J=7.4 Hz), 9.35 (d, 1H, J=7.5 Hz); 19F NMR (CDCl3):−44073; LCMS: purity: 96%; MS (m/e): 239 (M⁺).

7.1.792-Chloro-N4-(2,6-Dimethoxypyridin-3-yl)-5-fluoro-4-pyrimidineamine(R926889)

In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with3-amino-2.6-dimethoxypyridine gave2-chloro-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-4-pyrimidineamine. ¹HNMR (CDCl₃): δ 8.57 (d, 1H, J=8.7 Hz), 8.02 (d, 1H, J=2.7 Hz), 6.40 (d,1H, J=8.1 Hz), 4.03 (s, 3H), 3.98 (s, 3H); ¹⁹F NMR (CDCl₃): −44640;LCMS: purity: 90%; MS (m/e): 285 (M⁺).

7.1.80 2-Chloro-N4-(6-chloropyridin-3-yl)-5-fluoro-4-pyrimidineamine(R920400)

In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with3-amino-6-chloropyridine gave2-chloro-N4-(6-chloropyridin-3-yl)-5-fluoro-4-pyrimidineamine. ¹H NMR(CDCl₃): δ 8.53 (d, 1H, J=3 Hz), 8.25 (dd, 1H, J=3 and 9 Hz), 8.15 (d,1H, J=2.4 Hz), 7.39 (d, 1H, J=8.7 Hz), 7.00 (bs, 1H); LCMS: purity: 98%;MS (m/e): 259 (M⁺).

7.1.81 2-Chloro-5-fluoro-N4-(4-methylpyridin-2-yl)-4-pyrimidineamine(R920401)

In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with2-amino-4-methylpyridine gave2-chloro-5-fluoro-N4-(4-methylpyridin-2-yl)-4-pyrimidineamine. ¹H NMR(CDCl₃): δ 8.22 (s, 1H), 8.16 (d, 1H, J=8.4 Hz), 8.13 (d, 1H, J=2.4 Hz),6.91 (d, 1H, J=5.4 Hz), 2.42 (s, 3H); LCMS: purity: 87%; MS (m/e): 239(MH⁺).

7.1.82 2-Chloro-5-fluoro-N4-(3-trifluoromethoxyphenyl)-4-pyrimidineamine(R920402)

In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with3-trifluoromethoxyaniline gave2-chloro-5-fluoro-N4-(3-trifluoromethoxyphenyl)-4-pyrimidineamine. ¹HNMR (CDCl₃): δ 8.12 (d, 1H, J=3 Hz), 7.68 (bs, 1H), 7.53 (dd, 1H, J=1.2and 8.4 Hz), 7.41 9t, 1H, J=8.1 Hz), 7.04 (bdt, 2H); ¹⁹F NMR (CDCl₃):−16430 and −44463; LCMS: purity: 89%; MS (m/e): 308 (MH⁺).

7.1.832-Chloro-N4-(3,4-Difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine(R920403)

In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with3,4-difluoromethylenedioxyaniline gave2-chloro-N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine.¹H NMR (CDCl₃): δ 8.09 (d, 1H, J=3 Hz), 7.70 (d, 1H, J=2.4 Hz), 7.10(dd, 1H, J=2.4 and 8.7 Hz), 7.06 (t, 1H, J=8.1 Hz), 6.97 (bs, 1H); ¹⁹FNMR (CDCl₃): −14175 and −44562; LCMS: purity: 95%; MS (m/e): 304 (MH⁺).

7.1.84 2-Chloro-5-fluoro-N4-(quinolin-6-yl)-4-pyrimidineamine (R920409)

In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with 6-aminoquinoline gave2-chloro-5-fluoro-N4-(quinolin-6-yl)-4-pyrimidineamine. ¹H NMR (CDCl₃):δ 8.02 (dd, 1H, J=2.7 Hz), 8.00 (dd, 1H, J=2.4 Hz), 7.73 (d, 1H, J=9Hz), 7.68 (dd, 1H, J=2.4 and 8.7 Hz), 7.28 (t, 1H, J=10.5 Hz), 6.42 (d,1H, J=9.3 Hz); ¹⁹F NMR (CDCl₃): −44344; LCMS: purity: 91%; MS (m/e): 292(M⁺).

7.1.852-Chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamine

In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with3-chloro-4-trifluoromethoxyaniline gave2-chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamine.¹H NMR (CDCl₃): δ 8.15 (d, 1H, J=3.0 Hz), 7.86 (d, 1H, J=2.1 Hz), 7.61(dd, 1H, J=2.1 and 8.7 Hz), 7.35 (dd, 1H, J=1.2 and 8.7 Hz), 6.98 (bs,1H); LCMS: purity: 97%; MS (m/e): 342 (M+2H).

7.1.86 2-Chloro-N4-(4-chloro-3-methoxyphenyl)-5-fluoro-4-pyrimidineamine

In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with4-chloro-3-methoxyaniline gave2-chloro-N4-(4-chloro-3-methoxyphenyl)-5-fluoro-4-aminopyrimidine. LCMS:purity: 88%; MS (m/e): 288 (MH⁺).

7.1.872-Chloro-5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-4-pyrimidinediamine

In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with5-amino-2-(2-hydroxyethyloxy)pyridine gave2-chloro-5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.28 (d, 1H, J=2.4 Hz), 8.08 (m, 1H), 7.99 (m, 1H),7.00 (bs, 1H), 6.87 (bd, 1H), 4.47 (m, 2H), 3.97 (m, 2H).

7.1.882-Chloro-N4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-5-fluoro-4-pyrimidineamine(R926910)

In a like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and7-amino-1,2,3,4-tetrahydroisoquinoline were reacted to provide2-chloro-N4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-5-fluoro-4-pyrimidineamine.¹H NMR (CDCl₃): δ 8.08 (d, 1H, J=3.0 Hz), 7.95 (d, 1H, J=6.0 Hz),7.50-7.42 (m, 2H), 7.21 (d, 1H, J=8.4 Hz), 6.96-6.90 (m, 1H), 4.95 (s,2H), 4.04 (t, 2H, J=5.7 Hz), 2.99 (t, 2H, J=5.7 Hz); ¹⁹F NMR (282 MHz,CDCl₃): −42555, −44573; LCMS: purity: 98%; MS (m/e): 410 (MH⁺).

7.1.892-Chloro-5-fluoro-N4-[2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-4-pyrimidineamine(R926911)

In a like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and7-amino-2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline were reactedto provide2-chloro-5-fluoro-N4-[2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-4-pyrimidineamine.¹H NMR (CDCl₃): δ 8.03 (s, 1H), 7.50-7.26 (m, 2H), 7.19-7.11 (m, 2H),4.57 (s, 2H), 3.64 (t, 2H, J=5.7 Hz), 2.80 (t, 2H, J=5.7 Hz), 1.48 (s,9H); LCMS: purity: 89%; MS (m/e): 379 (M⁺).

7.1.902-Chloro-5-fluoro-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-4-pyrimidineamine(R926912)

A solution of2-chloro-5-fluoro-N4-[2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-4-pyrimidineaminein 40% trifluoroacetic acid/dichloromethane was stirred at rt for 30min. Removal of the solvent left an oily residue which was suspended inwater, made basic with NaHCO₃, and extracted with ethyl acetate.Purification by column chromatography over silica gel provided2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-4-pyrimidineamine.1H NMR (CDCl₃): δ 8.04 (d, 1H, J=3.0 Hz), 7.37 (dd, 1H, J=2.4 and 8.4Hz), 7.27 (d, 1H, J=1.5 Hz), 7.11 (d, 1H, J=8.4 Hz), 6.92 (s, 1H), 4.04(s, 2H), 3.15 (t, 2H, J=6.0 Hz), 2.79 (t, 2H, J=6.0 Hz); ¹⁹F NMR (282MHz, CDCl₃): −44648; LCMS: purity: 97%; MS (m/e): 279 (MH⁺).

7.1.912-Chloro-5-fluoro-N4-(4-methyl-3-trifluoromethylphenyl)-4-pyrimidineamine(R926920)

In a like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-methyl-3-trifluoromethylanilinewere reacted to provide2-chloro-5-fluoro-N4-(4-methyl-3-trifluoromethylphenyl)-4-pyrimidineamine.¹H NMR (CDCl₃): δ 8.10 (d, 1H, J=3.0 Hz), 7.85-7.78 (m, 2H), 7.33 (d,1H, J=9.3 Hz), 6.96 (bs, 1H), 2.48 (d, 3H, J=1.2 Hz); ¹⁹F NMR (282 MHz,CDCl₃): −17641, −44541; LCMS: purity: 97%; MS (m/e): 306 (MH⁺).

7.1.92 2-Chloro-5-fluoro-N4-(4-fluoro-3-methylphenyl)-4-pyrimidineamine(R926921)

In a like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-fluoro-3-methylaniline werereacted to provide2-chloro-5-fluoro-N4-(4-fluoro-3-methylphenyl)-4-pyrimidineamine. ¹H NMR(CDCl₃): δ 8.06 (d, 1H, J=2.4 Hz), 7.48-7.43 (m, 1H), 7.39 (dd, 1H,J=2.7 and 6.3 Hz), 7.03 (t, 1H, J=9.0 Hz), 6.84 (bs, 1H), 2.30 (d, 1H,J=1.8 Hz); ¹⁹F NMR (282 MHz, CDCl₃): −34285, −44676; LCMS: purity: 95%;MS (m/e): 257 (MH⁺).

7.1.93N4-[3-[(N-t-butoxycarbonyl)aminomethyl]-4-methylphenyl]-2-chloro-5-fluoro-4-pyrimidineamine(R926924)

In a like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and3-[(N-t-butoxycarbonyl)aminomethyl]-4-methylaniline were reacted toprovideN4-[3-[(N-t-butoxycarbonyl)aminomethyl]-4-methylphenyl]-2-chloro-5-fluoro-4-pyrimidineamine.¹H NMR (CDCl₃): δ 8.05 (d, 1H, J=3.0 Hz), 7.52 (d, 1H, J=9.3 Hz), 7.45(s, 1H), 7.19 (d, 1H, J=8.1 Hz), 6.96-6.89 (m, 1H), 4.80 (bs, 1H), 2.31(s, 2H), 1.46 (s, 9H); LCMS: purity: 97%; MS (m/e): 311 (M-(t-butyl)⁺).

7.1.942-Chloro-N4-[3-[[4-(ethoxycarbonyl)piperidino]methyl]phenyl]-5-fluoro-4-pyrimidineamine

In a like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and ethyl1-(3-aminobenzyl)piperidine-4-carboxylate were reacted to provide2-chloro-N4-[3-[[4-(ethoxycarbonyl)piperidino]methyl]phenyl]-5-fluoro-4-pyrimidineamine.LCMS: purity: 97%; MS (m/e): 394 (MH⁺).

7.1.95 2-Chloro-N4-[3-[4-(ethoxycarbonyl)piperidinocarbonyl]phenyl]-5-fluoro-4-pyrimidineamine

In a like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and3-[[4-(ethoxycarbonyl)piperidino]carbonyl]aniline were reacted toprovide2-chloro-N4-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-4-pyrimidineamine.LCMS: purity: 96%; MS (m/e): 407 (M⁺).

7.1.962-Chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-yl)-4-pyrimidineamine

In a manner similar to the preparation ofN4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-oxonaphthalen-7-yl)-4-pyrimidineaminewas reduced with Dibal-H to yield2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-yl)-4-pyrimidineamine.¹H NMR (CDCl₃): δ 8.05 (d, 1H, J=3.0 Hz), 7.59 (d, 1H, J=2.4 Hz), 7.14(d, 1H, J=8.1 Hz), 6.93 (bs, 1H), 4.82-4.78 (m, 1H), 2.82-2.71 (m, 2H),2.08-1.74 (m, 5H); ¹⁹F NMR (282 MHz, CDCl₃): −44661; LCMS: purity: 94%;MS (m/e): 294 (MH⁺).

7.1.972-Chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-oxonaphthalen-7-yl)-4-pyrimidineamine

In a like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 7-amino-1-tetralone were reacted toprovide2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-oxonaphthalen-7-yl)-4-pyrimidineamine.1H NMR (DMSO-d₆): δ 10.08 (s, 1H), 8.31 (d, 1H, J=3.3 Hz), 8.15 (d, 1H,J=2.4 Hz), 7.82 (dd, 1H, J=2.4 and 8.1 Hz), 7.36 (d, 1H, J=8.1 Hz), 2.91(t, 2H, J=6.0 Hz), 2.59 (t, 2H, J=6.0 Hz), 2.07-1.98 (m, 2H); LCMS:purity: 93%; MS (m/e): 294 (MH⁺).

7.1.982-Chloro-5-fluoro-N4-[3-(trifluoromethylthio)phenyl]-4-pyrimidineamine

In a like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 3-(trifluoromethylthio)aniline werereacted to provide2-chloro-5-fluoro-N4-[3-(trifluoromethylthio)phenyl]-4-pyrimidineamine.1H NMR (CDCl₃): δ 8.13 (bs, 1H), 7.92 (bs, 1H), 7.89-7.84 (m, 1H),7.48-7.45 (m, 2H), 7.04 (bs, 1H); LCMS: purity: 97%; MS (m/e): 325(MH⁺).

7.1.992-Chloro-5-fluoro-N4-[(3-dihydroxyboryl)phenyl)]-4-pyrimidineamine

In a like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 3-aminobenzeneboronic acid werereacted to provide2-chloro-5-fluoro-N4-[(3-dihydroxyboryl)phenyl)]-4-pyrimidineamine.

7.1.100 2-Chloro-5-fluoro-N4-[(1H)-indol-6-yl]-4-pyrimidineamine

In a like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 6-aminoindole were reacted toprovide 2-chloro-5-fluoro-N4-[(1H)-indol-6-yl]-4-pyrimidineamine. LCMS:purity: 92%; MS (m/e): 263 (MH⁺).

7.1.1012-Chloro-5-fluoro-N4-(2-hydroxy-4-methylphenyl)-4-pyrimidineamine

In a like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 3-hydroxy-4-methylaniline werereacted to provide2-chloro-5-fluoro-N4-(2-hydroxy-4-methylphenyl)-4-pyrimidineamine. LCMS:purity: 97%; MS (m/e): 255 (MH⁺).

7.1.1022-Chloro-5-fluoro-N4-[2-(methoxycarbonyl)-(1H)-indol-6-yl]-4-pyrimidineamine

In a like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and6-amino-2-(methoxycarbonyl)-(1H)-indole were reacted to provide2-chloro-5-fluoro-N4-[2-(methoxycarbonyl)-(1H)-indol-6-yl]-4-pyrimidineaminewhich was used without further purification. LCMS: purity: 65%; MS(m/e): 322 (MH⁺).

7.1.103N4-[3-(4-(2-Chloro-5-fluoropyrimidine)-N-aminomethylene)-phenyl]-2-chloro-5-fluoro-4-pyrimidineamine(R940298)

The reaction flask equipped with a magnetic stirring bar and a rubberseptum (to prevent loss of 2,4-dichloro-5-fluoropyrimidine and N₂ inletwas charged 3-aminobenzylamine (0.22 g, 1.79 mmol), MeOH (1 mL), H₂O (3mL) and 2,4-dichloro-5-fluoropyrimidine (0.3 g, 1.79 mmol). The reactionmixture was stirred at 80° C. for 30 min., cool to room temperature,diluted with H₂O (30 mL). Upon saturation with sodium chloride it wasextracted with ethyl acetate (3×20 mL), dried over anhydrous sodiumsulfate and the solvent was removed. The resulting residue was filteredthrough a pad of silica gel (200-400 mesh) using 1 to 3% MeOH in CH₂Cl₂to obtainN4-[3-(4-(2-chloro-5-fluoropyrimidine)-N-methylaminomethylene)-phenyl]-2-chloro-5-fluoro-4-pyrimidineamineR940298. ¹H NMR (DMSO-d6): δ 10.09 (1H, s), 8.88 (1H, t, J=5.85 Hz),8.40 (1H, d, J=3.6 Hz), 8.23 (1H, d, J=3.3 Hz), 7.74 (1H, s), 7.70 (1H,d, J=8.1 Hz), 7.44 (1H, t, J=7.8 Hz), 7.19 (1H, d, J=8.1 Hz), 4.69 (2H,d, J=5.7 Hz; purity 92%.

7.1.1042-Chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine(R940302)

The reaction flask equipped with a magnetic stirring bar and a rubberseptum (to prevent loss of 2,4-dichloro-5-fluoropyrimidine and N₂ inletwas charged with 3-methyloxycarbonyl-4-methoxyaniline (0.88 g, 4.86mmol), MeOH (3 mL), H₂O (7 mL) and 2,4-dichloro-5-fluoropyrimidine (0.81g, 4.86 mmol). The reaction mixture was stirred at 60° C. for 30 min.,diluted with H₂O (50 mL), acidified with 2N HCl (6 mL) and sonicated.The solid obtained was filtered, washed with H₂O and dried to produce2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamineR940302. ¹H NMR (DMSO-d6): δ 10.10 (1H, s), 8.39 (1H, d, J=3.6 Hz), 8.04(1H, d, J=2.7 Hz), 7.98-7.93 (1H, m), 7.30 (1H, d, J=9 Hz), 3.92 (3H,s), 3.89 (3H, m); purity 96%; MS (m/e): 312 (MH⁺).

7.1.105 2-Chloro-5-fluoro-N4-(4-phahthlimide)-4-pyrimidineamine(R940303)

In like manner to the preparation of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-aminophthalimide were reacted toproduce 2-chloro-5-fluoro-N4-(4-phahthlimide)-4-pyrimidineamine R940303.¹H NMR (DMSO-d6): δ 11.38 (1H, s), 10.60 (1H, s), 8.57 (1H, d, J=3.3Hz), 8.39 (1H, d, J=1.8 Hz), 8.18 (1H, dd, J=8.4 Hz, J=2.1 Hz), 7.93(1H, d, J=8.1 Hz); purity 90%; MS (m/e): 293 (MH⁺).

7.1.1062-Chloro-5-fluoro-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-4-pyrimidineamine(R940305)

In like manner to the preparation of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and3-methylaminocarbonyl-4-methoxyaniline were reacted to produce2-chloro-5-fluoro-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-4-pyrimidineamineR940305. ¹H NMR (DMSO-d6): δ 9.91 (1H, s), 8.31 (1H, d, J=3.6 Hz), 8.11(1H, d, J=2.7 Hz), 7.78 (1H, dd, J=9 Hz, J=2.7 Hz), 7.59 (1H, m), 6.87(1H, d, J=9 Hz), 3.90 (3H, s), 2.96 (3H, d, J=4.5 Hz); purity 93%.

7.1.107N2-Chloro-5-fluoro-N4-[3-(N-morpholinomethylene)-4-methoxyphenyl]-4-pyrimidineamine(R940313)

In like manner to the preparation of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and3-(N-morpholinomethylene)-4-methoxyaniline were reacted to produce2-chloro-5-fluoro-N4-[3-(N-morpholinomethylene)-4-methoxyphenyl]-4-pyrimidineamineR940313. ¹H NMR (DMSO-d6): δ 10.00 (1H, s), 8.35 (1H, d, J=3.3 Hz), 7.72(1H, d, J=3 Hz), 7.58 (1H, d, J=9.3 Hz), 7.12 (1H, d, J=8.4 Hz), 3.89(3H, s), 3.8-3.5 (6H, m), 2.58 (4H, m); purity 96%; MS (m/e): 352 (M).

7.1.108N4-[3-(N-tert-Butoxycarbonyl-N-methylaminomethylene)-phenyl]-2-chloro-5-fluoro-4-pyrimidineamine(R940315)

In like manner to the preparation of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and3-(N-tert-butoxycarbonyl-N-methylaminomethylene)-aniline were reacted toproduceN4-[3-(N-tert-butoxycarbonyl-N-methylaminomethylene)-phenyl]-2-chloro-1-fluoro-4-pyrimidineamineR940315. ¹H NMR (DMSO-d6): δ 10.13 (1H, s), 8.42 (1H, d, J=3.6 Hz), 7.69(1H, m), 7.64 (1H, s), 7.45 (1H, t, J=7.6 Hz), 7.09 (1H, d, J=7.8 Hz),4.48 (2H, s), 2.90 (3H, s), 1.49 (9H, m); purity 92%; MS (m/e): 367(MH⁺).

7.1.109N4-(3-(N-tert-Butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine(R940320)

In like manner to the preparation of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and3-(N-tert-butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxy-anilinewere reacted to produceN4-(3-(N-tert-butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamineR940320. ¹H NMR (DMSO-d6): δ 10.01 (1H, s), 8.34 (1H, d, J=3.6 Hz), 7.52(2H, m), 7.08 (1H, d, J=8.7 Hz), 4.33 (3H, m), 3.90 (3H, s), 1.50-1.30(9H, m), 1.18 (6H, d, J=6.9 Hz); purity 95%.

7.1.1102-Chloro-N4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamine(R940322)

In like manner to the preparation of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and6-amino-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one were reacted to produce2-chloro-N4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineR940322. ¹H NMR (DMSO-d6): δ 10.89 (1H, s), 10.04 (1H, s), 8.38 (1H, d,J=3.6 Hz), 7.35 (2H, m), 7.04 (1H, d, J=8.4 Hz), 1.50 (6H, s); purity91.4%; MS (m/e): 322 (M).

7.1.1112-Chloro-N4-[3-dihydro-2,2-dimethyl-4-(2-(pyridyl-1-oxide)-benzo[1,4]oxazin-6-yl]-5-fluoro-4-pyrimidineamine(R940328)

In like manner to the preparation of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and2-(6-amino-3-dihydro-2,2-dimethyl-benzo[1,4]oxazin-4-yl)pyridine 1-Oxidewere reacted to produce2-chloro-N4-[3-dihydro-2,2-dimethyl-4-(2-(pyridyl-1-oxide)-benzo[1,4]oxazin-6-yl]-5-fluoro-4-pyrimidineamineR940328. ¹H NMR (DMSO-d6): δ 9.82 (1H, s), 8.39 (1H, dd, J=6.3 Hz, J=1.2Hz), 8.30 (1H, d, J=3.6 Hz), 7.63 (1H, dd, J=8.4 Hz, J=2.4 Hz), 7.47(1H, td, J=7.5 Hz, J=1.8 Hz), 7.34 (1H, m), 7.21 (1H, dd, J=8.7 Hz,J=2.4 Hz), 7.07 (1H, d, J=2.7 Hz), 6.91 (1H, d, J=8.7 Hz), 3.64 (2H, s),1.41 (6H, s); purity 95.8%; MS (m/e): 402 (MH⁺).

7.1.1122-Chloro-N4-[3-dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazin-6-yl]-5-fluoro-4-pyrimidineamine(R940336)

In like manner to the preparation of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and6-amino-3-dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazine werereacted to produce2-chloro-N4-[3-dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazin-6-yl]-5-fluoro-4-pyrimidineamineR940336. ¹H NMR (DMSO-d6): δ 9.95 (1H, s), 8.38 (1H, dd, J=4.8 Hz, J=1.8Hz), 8.33 (1H, d, J=3.6 Hz), 7.84 (1H, d, J=2.1 Hz), 7.79 (1H, ddd,J=15.6 Hz, J=7.2 Hz, J=2.1 Hz), 7.57 (1H, d, J=8.4 Hz), 7.19 (1H, dd,J=8.4 Hz, J=2.4 Hz), 7.01-6.95 (2H, m), 3.96 (2H, s), 1.32 (6H, s);purity 99.3%; MS (m/e): 386 (MH⁺).

7.1.1132-Chloro-N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamine(R940342)

In like manner to the preparation of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one were reacted to produce2-chloro-N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineR940342. ¹H NMR (DMSO-d6): δ 12.24 (1H, s), 10.23 (1H, s), 8.45 (1H, dd,J=3.3 Hz, J=0.9 Hz), 7.66 (1H, dd, J=4.2 Hz, J=2.4 Hz), 7.55 (1H, dt,J=9 Hz, J=2.5 Hz), 7.43 (1H, d, J=9 Hz+); ¹⁹F NMR (DMSO-d6): δ −21582,−43415; purity 96.2%; MS (m/e): 331 (MH⁺).

7.1.1142-Chloro-N4-[(2,2-dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-7-yl]-5-fluoro-4-pyrimidineamine(R940344)

In like manner to the preparation of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and7-amino-2,2-dimethyl-4H-5-pyrido[1,4]oxazin-3-one were reacted toproduce2-chloro-N4-[(2,2-dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-7-yl]-5-fluoro-4-pyrimidineamineR940344. ¹H NMR (DMSO-d6): δ 11.32 (1H, s), 10.20 (1H, s), 8.45 (1H, d,J=3.6 Hz), 8.33 (1H, d, J=2.1 Hz), 7.84 (1H, d, J=2.1 Hz), 1.54 (6H, s);purity 90.8%; MS (m/e): 324 (MH⁺).

7.1.115N4-(4-Aminocarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine(R945028)

In a manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine (250 mg, 1.50 mmol) and4-aminocarbonylmethyleneoxyaniline (540 mg, 3.25 mmol) were reacted toyieldN4-(4-aminocarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine.LCMS: ret. time: 18.34 min.; purity: 100%; MS (m/e): 298.47 (MH⁺).

7.1.1162-Chloro-5-fluoro-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-6-yl]-4-pyrimidineamine(R945298)

In a manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and6-amino-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one were reacted to yield2-chloro-5-fluoro-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-6-yl]-4-pyrimidineamine.¹H NMR (DMSO-d₆): δ 4.63 (s, 2H), 7.34 (d, J=8.7 Hz, 1H), 7.44 (d, J=8.4Hz, 1H), 8.33 (d, J=3.3 Hz, 1H), 10.14 (s, 1H, NH), 11.19 (s, 1H, NH);¹⁹F NMR (282 MHz, DMSO-d₆): δ −152.35; LCMS: ret. time: 26.74 min.;purity: 85.90%; MS (m/e): 296.13 (MH⁺).

7.1.117 N4-(1,4-Benzoxazin-6-yl)-N2-chloro-5-fluoropyrimidineamine

In like manner to2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 6-amino-1,4-benzoxazine were reactedto yield N4-(1,4-Benzoxazin-6-yl)-N2-chloro-5-fluoropyrimidineamine 1HDMSO 8.2 (d, 1H), 6.8 (m, 1H), 6.75 (m, 1H), 6.60 (m, 1H), 4.05 (m, 2H),3.2 (m, 2H) purity 95% MS (m/e): 281 (MH⁺).

7.1.118 N4-(1,4-Benzoxazin-7-yl)]-N2-chloro-5-fluoropyrimidineamine

In like manner to2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 7-amino-1,4-benzoxazine were reactedto yield N4-(1,4-Benzoxazin-7-yl)]-N2-chloro-5-fluoropyrimidineamine 1HDMSO 8.2 (d, 1H), 6.8 (m, 1H), 6.75 (m, 1H), 6.60 (m, 1H), 4.05 (m, 2H),3.2 (m, 2H) purity 94% MS (m/e):281 (MH⁺).

7.1.119 N4-(1,4-Benzoxazin-3-on-6-yl)-N2-chloro-5-fluoropyrimidineamine

In like manner to2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 6-amino-1,4-benzoxazine-3-one werereacted to yieldN4-(1,4-Benzoxazin-3-on-6-yl)-N2-chloro-5-fluoropyrimidineamine 1H DMSO8.2 (d, 1H), 6.8 (m, 1H), 6.75 (m, 1H), 6.60 (m, 1H), 4.73 (s, 2H)purity 96% MS (m/e): 295 (MH⁺).

7.1.120 N4-(1,4-Benzoxazin-3-on-7-yl)-N2-chloro-5-fluoropyrimidineamine

In like manner to2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 7-amino-1,4-benzoxazine-3-one werereacted to yieldN4-(1,4-Benzoxazin-3-on-7-yl)-N2-chloro-5-fluoropyrimidineamine 1H DMSO8.2 (d, 1H), 6.8 (m, 1H), 6.79 (m, 1H), 6.6 (m, 1H), 4.68 (s, 2H) purity93% MS (m/e): 295 (MH⁺).

7.1.121N2-Chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-6-yl)-pyrimidineamine

In like manner to2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 6-amino-4-N-methyl-1,4-benzoxazinewere reacted to yieldN2-Chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-6-yl)-pyrimidineamine 1HDMSO 8.2 (d, 1H), 6.8 (m, 1H), 6.75 (m, 1H), 6.60 (m, 1H), 4.05 (m, 2H),3.2 (m, 2H) 2.8 (s, 3H) purity 95% MS (m/e): 295 (MH⁺).

7.1.122N2-Chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-7-yl)-pyrimidineamine

In like manner to2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 7-amino-4-N-methyl-1,4-benzoxazinewere reacted to yieldN2-Chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-7-yl)-pyrimidineamine 1HDMSO 8.2 (d, 1H), 6.8 (m, 1H), 6.75 (m, 1H), 6.60 (m, H), 4.05 (m, 2H),3.2 (m, 2H) 2.8 (s, 3H) purity 94% MS (m/e): 295 (MH⁺).

7.1.123N2-Chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-3-on-6-yl)-pyrimidineamine

In like manner to2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and6-amino-4-N-methyl-1,4-benzoxazine-3-one were reacted to yieldN2-Chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-3-on-6-yl)-pyrimidineamine1H DMSO 8.2 (d, 1H), 6.8 (m, 1H), 6.75 (m, 1H), 6.60 (m, 1H), 4.73 (s,2H) 2.8 (s, 3H) purity 96% MS (m/e): 309 (MH⁺).

7.1.124N2-Chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)-pyrimidineamine

In like manner to2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and7-amino-4-N-methyl-1,4-benzoxazine-3-one were reacted toN2-Chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)-pyrimidineamine1H DMSO 8.2 (d, 1H), 6.8 (m, 1H), 6.75 (m, 1H), 6.60 (m, H), 4.68 (s,2H) 2.8 (s, 3H) purity 93% MS (m/e): 309 (MH⁺).

7.1.125N2-chloro-N4-(3-ethylcarboxy-4H-imidazo[5,1-c]-1,4-benzoxazin-6-yl)-5-fluoropyrimidinediamine(R909258)

In like manner to2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and ethyl6-amino-3-carboxy-4H-imidazo[5,1-c]-1,4-benzoxazine were reacted toyieldN2-chloro-N4-(3-ethylcarboxy-4H-imidazo[5,1-c]-1,4-benzoxazin-6-yl)-5-fluoropyrimidinediamine1H (DMSO-d6) 8.42 (s, 1H), 8.30 (m, 1H), 8.05 (m, 1H), 7.43 (m, 1H),5.53 (s, 2H), 4.25 (q, 2H J=6.5 Hz), 1.28 (t, 2H, J=6.5 Hz), purity 90%MS (m/e): 390 (MH⁺).

7.1.126N2-Chloro-N4-(3,3-dimethyl-1,4-benzoxazin-6-yl)-5-fluoro-pyrimidineamine

In like manner to2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 6-Amino-3,3-dimethyl-1,4-benzoxazinewere reacted to yieldN2-Chloro-N4-(3,3-dimethyl-1,4-benzoxazin-6-yl)-5-fluoro-pyrimidineamine1H DMSO 8.18 (d, 1H), 6.8 (d, 1H), 6.67 (m, 2H), 3.76 (s, 2H), 1.05 (s,6H) purity 99% MS (m/e): 309 (MH⁺)

7.1.1272-Chloro-5-fluoro-N-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-4-pyrimidineamine(R935241)

In like manner to the preparation of2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine was reacted with5-amino-1-(methoxycarbonyl)methyl-indazoline to produce2-chloro-5-fluoro-N-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-4-pyrimidineamine.¹H NMR (DMSO-d₆): δ 10.04 (s, 1H), 8.28 (d, 1H, J=3.5 Hz), 8.12 (s, 1H),8.00 (dd, 1H, J=1.2 and 4.1 Hz), 7.64 (d, 1H, J=8.8 Hz), 7.58-7.54 (m,1H), 5.39 (s, 2H), 3.66 (s, 3H).

7.1.1282-Chloro-5-fluoro-N-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-4-pyrimidineamine(R935257)

In like manner to the preparation of2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine was reacted with8-amino-4H-imidazo[2,1-c][1,4]-benzoxazine to produce2-chloro-5-fluoro-N-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-4-pyrimidineamine.¹H NMR (DMSO-d₆): ¹H NMR (DMSO-d₆): δ 10.08 (s, 1H), 8.31 (s, 1H), 7.91(d, 1H, J=2.3 Hz), 7.74 (d, 1H, J=1.2 Hz), 7.37 (dd, 1H, J=2.3 and 8.8Hz), 7.16 (d, 1H, J=8.8 Hz), 7.14 (d, 1H, J=1.2 Hz), 5.29 (s, 2H). LCMS:ret. time: 18.74 min.; purity: 99%; MS (m/e): 318 (MH⁺).

7.1.129 2-Chloro-5-fluoro-N-(indazoline-6-yl)-4-pyrimidineamine(R935260)

In like manner to the preparation of 2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine was reacted with 6-aminoindazole toproduce 2-chloro-5-fluoro-N-(indazoline-6-yl)-4-pyrimidineamine. ¹H NMR(CDCl₃): δ 13.03 (s, 1H), 10.07 (s, 1H), 8.32 (d, 1H, J=3.5 Hz), 8.07(s, 1H), 7.99 (s, 1H), 7.71 (d, 1H, J=8.8 Hz), 7.34 (dd, 1H, J=1.7 and8.8 Hz). LCMS: ret. time: 18.52 min.; purity: 99%; MS (m/e): 263 (MH⁺).

7.1.130 2-Chloro-5-fluoro-N-(indazoline-5-yl)-4-pyrimidineamine(R935265)

In like manner to the preparation of 2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine was reacted with 5-aminoindazoline. ¹HNMR (CDCl₃): δ 9.99 (s, 1H), 8.26 (d, 1H, J=3.5 Hz), 8.07 (s, 1H), 7.99(d, 1H, J=1.1 Hz), 7.53 (dd, 2H, J=1.7 and 8.8 Hz). LCMS: ret. time:18.03 min.; purity: 97%; MS (m/e): 264 (MH⁺).

7.1.131 2-Chloro-5-fluoro-N-(1H-pyrrol-1-yl)-4-pyrimidineamine (R935275)

In like manner to the preparation of 2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine was reacted with 1-aminopyrrole toproduce 2-chloro-5-fluoro-N-(1H-pyrrol-1-yl)-4-pyrimidineamine. ¹H NMR(CDCl₃): δ 11.39 (s, 1H), 8.35 (d, 1H, J=3.5 Hz), 6.83 (t, 2H, J=2.3Hz), 6.07 (t, 2H, J=2.3 Hz). LCMS: ret. time: 18.95 min.; purity: 97%;MS (m/e): 213 (MH⁺).

7.1.1322-Chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine(R926853)

A reaction mixture containing 2,4-dichloro-5-fluoro-pyrimindine (1.2equivalents) and 3-(tetrazol-5-yl)aniline (1 equivalents) inmethanol:water (1:1; v/v) was heated at 60° C. for 24 h. Upon dilutionwith water and acidification, the solid formed was filtered, washed withwater, dried and analyzed to give2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine(R926853). Alternatively this reaction can be achieved by treating2,4-dichloro-5-fluoropyrimidine (1 equivalent) with3-(tetrazol-5-yl)aniline (3 equivalents) in methanol:water (1:1; v/v) at60° C. for 2-3 hours or at room temperature for 24 h to give2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine. ¹HNMR (DMSO-d6): δ 10.25 (s, 1H), 8.43 (s, 1H), 8.37 (d, 1H, J=3.6 Hz),7.90 (dd, 1H, J=0.9 and 9 Hz), 7.75 (d, 1H, J=7.5 Hz), 7.61 (t, 1H,J=7.8 Hz); LCMS: purity: 90%; MS (m/e): 292 (MH⁺).

7.1.1332-Chloro-N4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-2,4-pyrimidineamine(R950297)

A solution of 3,4-dihydro-4-hydroxy-6-amino-2H-1-benzopyran and2,4-dichloro-5-fluoro-pyrimidine in MeOH was stirred for 2 hours at 70°C. The mixture was diluted with water and the resulting precipitate wasfiltered to give2-chloro-N4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-2,4-pyrimidineamineas a pale brown solid. LCMS: purity: 99.3%; MS (m/e): 296.1 (MH⁺).

7.1.1342-Chloro-N4-(4-methoxycarbonylethyleneoxyphenyl)-5-fluoro-2,4-pyrimidineamine(R950375)

A solution of 3-(p-aminophenyl)-propionic acid and2,4-dichloro-5-fluoro-pyrimidine in MeOH was stirred for 2 hours at 70°C. The mixture was diluted with water and the resulting precipitate wasfiltered to give2-chloro-N4-(4-methoxycarbonylethyleneoxyphenyl)-5-fluoro-2,4-pyrimidineamineas a pale brown solid. LCMS: purity: 93.3%; MS (m/e): 311.98 (M⁻).

7.1.1352-Chloro-N4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidineamine(R950298)

A solution of 3-carboxy-4-hydroxyaniline and2,4-dichloro-5-fluoro-pyrimidine in MeOH was stirred for 2 hours at 70°C. The mixture was diluted with water and the resulting precipitate wasfiltered to give2-chloro-N4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidineamine asa pale brown solid. LCMS: purity: 87.4%; MS (m/e): 284.1 (MH⁺).

7.1.1362-Chloro-N4-(4-trifluoromethyl-3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidineamine(R950390)

A solution of 4-trifluoromethyl-3-methoxycarbonylaniline and2,4-dichloro-5-fluoro-pyrimidine in MeOH was stirred for 2 hours at 70°C. The mixture was diluted with water and the resulting precipitate wasfiltered to give2-chloro-N4-(4-trifluoromethyl-3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidineamineas a pale brown solid. LCMS: purity: 96.4%; MS (m/e): 366.34 (MH⁺).

7.1.1372-Chloro-N4-(3-methylcarbonylphenyl)-5-fluoro-2,4-pyrimidineamine(R950369)

A solution of 3-methylcarbonylaniline and2,4-dichloro-5-fluoro-pyrimidine in MeOH was stirred for 2 hours at 70°C. The mixture was diluted with water and the resulting precipitate wasfiltered to give2-chloro-N4-(3-methylcarbonylphenyl)-5-fluoro-2,4-pyrimidineamine as apale brown solid. LCMS: purity: 99.1%; MS (m/e): 266.12 (MH⁺).

7.1.1382-Chloro-N4-(3-phenylcarbonylphenyl)-5-fluoro-2,4-pyrimidineamine(R950370)

A solution of 3-phenylcarbonylaniline and2,4-dichloro-5-fluoro-pyrimidine in MeOH was stirred for 2 hours at 70°C. The mixture was diluted with water and the resulting precipitate wasfiltered to give2-chloro-N4-(3-phenylcarbonylphenyl)-5-fluoro-2,4-pyrimidineamine as apale brown solid. LCMS: purity: 78.5%; MS (m/e): 328.16 (MH⁺).

7.1.139 2-Chloro-N4-(3-nitrophenyl)-5-fluoro-2,4-pyrimidineamine

A solution of 3-nitroaniline and 2,4-dichloro-5-fluoro-pyrimidine inMeOH was stirred for 2 hours at 70° C. The mixture was diluted withwater and the resulting precipitate was filtered to give2-chloro-N4-(3-nitrophenyl)-5-fluoro-2,4-pyrimidineamine as a pale brownsolid. ¹H NMR (DMSO): δ 10.34 (s, 1H), 8.73 (d, 1H, J=2.4 Hz), 7.66-8.29(m, 4H).

7.1.1402-Chloro-N4-(3-hydroxymethylen-4-methoxyphenyl)-5-fluoro-4-aminopyridine(R950384)

A solution of 3-hydroxymethylen-4-methoxyaniline and2,4-dichloro-5-fluoro-pyrimidine in MeOH was stirred for 2 hours at 70°C. The mixture was diluted with water and the resulting precipitate wasfiltered to give2-chloro-N4-(3-hydroxymethylen-4-methoxyphenyl)-5-fluoro-4-aminopyridineas a pale brown solid. LCMS: purity: 91.8%; MS (m/e): 266.03 (MH⁻).

7.1.141 2-Chloro-N4-(3-amino-4-ethoxyphenyl)-5-fluoro-4-aminopyridine(R950387)

A solution of 3-amino-4-ethoxyaniline and2,4-dichloro-5-fluoro-pyrimidine in MeOH was stirred for 2 hours at 70°C. The mixture was diluted with water and the resulting precipitate wasfiltered to give2-chloro-N4-(3-amino-4-ethoxyphenyl)-5-fluoro-4-aminopyridine as a palebrown solid. LCMS: purity: 93.2%; MS (m/e): 252.06 (MH⁻).

7.2 Synthesis of Amines and Amine Precursors 7.2.15-Amino-2-(2-hydroxyethyleneoxy)pyridine

A methanolic solution (50 mL) of2-(2-hydroxyethyleneoxy)-5-nitropyridine (0.5 g) was hydrogenated in thepresence of Pd/C (10%; 0.05 g) using a balloon filled with hydrogen for2 h. After the filtration through a pad of celite and washing withmethanol the solution was concentrated to give the5-amino-2-(2-hydroxyethyloxy)pyridine. ¹H NMR (CDCl₃): δ 7.58 (d, 1H,J=3 Hz), 7.05 (dd, 1H, J=2.7 and 8.1 Hz), 6.64 (d, 1H, J=8.7 Hz), 4.36(m, 2H), 3.89 (m, 2H).

7.2.2 4-Chloro-3-methoxyaniline

In like manner to the preparation of5-amino-2-(2-hydroxyethyleneoxy)pyridine, the hydrogenation of4-chloro-3-methoxynitrobenzene gave 4-chloro-3-methoxyaniline. LCMS:purity: 98%; MS: 199 (M+acetonitrile).

7.2.3 2-[5-Amino-2-oxo-1,3-benzoxazol-3(2H)-yl]acetamide

In like manner to the preparation of5-amino-2-(2-hydroxyethyleneoxy)pyridine, the hydrogenation of2-[1,3-benzoxazol-2-oxo-5-nitro-3 (2H)-yl)acetamide gave2-[5-amino-2-oxo-1,3-benzoxazol-3(2H)-yl]acetamide. LCMS: purity: 96%;MS: 208 (MH⁺).

7.2.4 7-nitro-1,2,3,4-tetrahydroisoquinoline

7-nitro-1,2,3,4-tetrahydroisoquinoline was prepared by nitration of1,2,3,4-tetrahydroisoquinoline according to the following reference:Grunewald, Gary L.; Dahanukar, Vilas H.; Caldwell, Timothy M.;Criscione, Kevin R.; Journal of Medicinal Chemistry (1997), 40(25),3997-4005.

7.2.5 2-(t-Butoxycarbonyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline

A mixture of 7-nitro-1,2,3,4-tetrahydroisoquinoline (0.55 g, 3.1 mmole),di-t-butyldicarbonate (0.70 g, 3.2 mmole), triethylamine (1.0 mL, 7.7mmole) in dichloromethane (8 mL) was stirred at rt for 8 h. The reactionmixture was diluted with water (50 mL) and stirred for 1 h. The organicphase was separated and washed with brine. Concentration of the organicphase gave 2-(t-butoxycarbonyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline.¹H NMR (CDCl₃): δ 8.03-7.95 (m, 2H), 7.28 (d, 1H, J=8.4 Hz), 4.66 (s,2H), 3.68 (t, 2H, J=6.0 Hz), 2.92 (t, 2H, J=6.0 Hz), 1.49 (s, 9H).

7.2.6 2,3-Dihydro-6-nitro-4-benzypyranon

3-(p-Nitrophenyl)-propionic acid is dissolved in concentrated sulfuricacid and treated with P₂O₅. The mixture is stirred for 1 hr at roomtemperature and poured onto ice. Filtration gave2,3-dihydro-6-nitro-4-benzypyranon as a white solid. ¹H NMR (DMSO): δ8.47 (d, J=3.0 Hz, 1H), 8.35 (dd, J=3.0, 9.0 Hz, 1H), 7.29 (d, J=9.0 Hz,1H), 4.70 (t, J=7.2 Hz, 1H), 2.90 (t, J=7.2 Hz, 1H).

7.2.7 3,4-Dihydro-4-hydroxy-6-amino-2H-1-benzopyran

A mixture 2,3-dihydro-6-nitro-4-benzypyranon and Pd/C (10%) in MeOH washydrogenated at 22° C. for 3 hours (40 psi). The mixture was filteredand concentrated to dryness to give3,4-dihydro-4-hydroxy-6-amino-2H-1-benzopyran as a brown oil. ¹H NMR(DMSO): δ 6.40-6.56 (m, 3H), 5.05 (bs, 1H), 4.45 (bs, 1H), 3.94-4.09 (m,2H), 1.76-1.98 (m, 2H).

7.2.8N4-(3,4-Ethylenedioxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R950287)

A solution of2-Chloro-5-ethoxycarbonyl-N4-(3,4-ethylenedioxyphenyl)-2,4-pyrimidineaminein EtOH was treated with a 25% aqueous solution of NH₃. The mixture wasstirred for 30 min at 100° C. and purified by flash chromatography onsilica gel to giveN4-(3,4-ethylenedioxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine as awhite solid. LCMS: purity: 92.3%; MS (m/e): 317.28 (MH⁺, 100).

7.2.9 3-(N-morpholinocarbonyl)aniline

To a 0° C. solution of 3-nitrobenzoylchloride (0.50 g, 2.7 mmole) andpyridine (0.27 mL, 3.2 mmole) in anhydrous dichloromethane (15 mL) wasadded morpholine (0.28 mL, 3.2 mmole). The reaction mixture was allowedto warm to rt and was stirred for 20 h. The solvents were removed undervacuum and the residue suspended in ethyl acetate and washed with 1NHCl. The organic layer was washed with a saturated solution of NaHCO₃and brine. Removal of the solvents under vacuum provided1-(N-morpholinocarbonyl)-3-nitrobenzene which was used without furtherpurification.

A mixture of 1-(N-morpholinocarbonyl)-3-nitrobenzene (0.64 g) and 10% Pdon activated carbon (60 mg) in degassed methanol (65 mL) was stirredunder a balloon of H₂ for 2 h. The reaction mixture was filtered throughCelite® filter aid and then concentrated under reduced pressure toprovide 3-(N-morpholinocarbonyl)aniline in quantitative yield. ¹H NMR(CDCl₃): δ 7.19-7.14 (m, 1H), 6.75-6.69 (m, 3H), 3.58-3.71 (m, 10H).

7.2.10 3-(N-propylcarbonyl)aniline

In like manner to the preparation of 3-(N-morpholinocarbonyl)aniline,3-nitrobenzoylchloride and n-propylamine were reacted to prepare1-[(N-propylamino)carbonyl]-3-nitrobenzene which underwent hydrogenationto provide 3-(N-propylcarbonyl)aniline. 1H NMR (CDCl₃): δ 7.18 (t, 1H,J=7.5 Hz), 7.13 (t, 1H, J=1.8 Hz), 7.05-7.01 (m, 1H), 6.78 (ddd, 1H,J=1.2, 2.4, and 7.5 Hz), 6.10 (bs, 1H), 3.58-3.53 (bs, 2H), 3.43-3.34(m, 2H), 1.68-1.57 (m, 2H), 0.97 (t, 3H, J=7.2 Hz).

7.2.11 3-[4-(Ethoxycarbonyl)piperidinocarbonyl]aniline

In like manner to the preparation of 3-(N-morpholinocarbonyl)aniline,3-nitrobenzoylchloride and ethyl isonipecotate were reacted to prepare1-[4-(ethoxycarbonyl)piperidinocarbonyl]-3-nitrobenzene which underwenthydrogenation to provide3-[4-(ethoxycarbonyl)piperidinocarbonyl]aniline.

7.2.12 3-(N-methylcarbonyl)aniline

In like manner to the preparation of 3-(N-morpholinocarbonyl)aniline,3-nitrobenzoylchloride and methylamine hydrochloride were reacted toprepare 1-[(N-methylamino)carbonyl]-3-nitrobenzene which underwenthydrogenation to provide 3-(N-methylcarbonyl)aniline. ¹H NMR (CDCl₃): δ7.18 (t, 1H, J=7.5 Hz), 7.13 (t, 1H, J=1.8 Hz), 7.04-6.99 (m, 1H),6.81-6.75 (m, 1H), 6.05 (bs, 1H), 3.84 (bs, 2H), 2.99 (d, 3H, J=4.8 Hz).

7.2.13 7-Amino-1-tetralone

In like manner to the preparation of ethyl 4-aminophenoxyacetate,hydrogenation of 7-nitro-1-tetralone was carried out to prepare7-amino-1-tetralone. ¹H NMR (CDCl₃): δ 7.32 (d, 1H, J=2.4 Hz), 7.05 (d,1H, J=8.1 Hz), 6.82 (dd, 1H, J=2.4 and 8.1 Hz), 2.85 (t, 2H, J=6.6 Hz),2.61 (t, 2H, J=6.6 Hz), 2.14-2.04 (m, 2H).

7.2.14 7-Amino-2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline

In like manner to the preparation of ethyl 4-aminophenoxyacetate,hydrogenation of2-(t-butoxycarbonyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline was carriedout to prepare7-amino-2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline. ¹H NMR(CDCl₃): δ 6.92 (d, 1H, J=8.4 Hz), 6.52 (dd, 1H, J=2.4 and 8.4 Hz), 6.44(bs, 1H), 4.47 (s, 2H), 3.63-3.48 (m, 2H), 2.71 (t, 2H, J=5.1 Hz), 1.45(s, 9H).

7.2.15 7-Amino-1,2,3,4-tetrahydroisoquinoline

In like manner to the preparation of ethyl 4-aminophenoxyacetate,hydrogenation of 7-nitro-1,2,3,4-tetrahydroisoquinoline was carried outto prepare 7-amino-1,2,3,4-tetrahydroisoquinoline. ¹H NMR (DMSO-d₆): δ9.35 (bs, 1H), 6.82 (d, 1H, J=8.1 Hz), 6.45 (dd, 1H, J=2.4 and 8.4 Hz),6.30 (d, 1H, J=2.4 Hz), 5.05 (s, 2H), 4.05 (s, 2H), 3.24 (t, 2H, J=6.6Hz), 2.78 (t, 2H, J=6.6 Hz).

7.2.16 2-(3-aminophenoxy)-N,2-dimethylpropanamide

In like manner to the preparation of ethyl 4-aminophenoxyacetate,hydrogenation of N,2-dimethyl-2-(3-nitrophenoxy)propanamide was carriedout to prepare 2-(3-aminophenoxy)-N,2-dimethylpropanamide. ¹H NMR(CDCl₃): δ 7.03 (t, 1H, J=7.8 Hz), 6.71 (bs, 1H), 6.39 (dd, 1H, J=1.2and 6.9 Hz), 6.29 (dd, 1H, J=2.4 and 9.6 Hz), 6.25-6.22 (m, 1H), 2.86(d, 3H, J=4.2 Hz), 2.86 (d, 3H, J=4.2 Hz), 1.50 (s, 6H).

7.2.17 Ethyl 2-(3-aminophenoxy)-2-methylpropanate

In like manner to the preparation of ethyl 4-aminophenoxyacetate,hydrogenation of ethyl 2-methyl-2-(3-nitrophenoxy)propanate was carriedout to prepare ethyl 2-(3-aminophenoxy)-2-methylpropanate. ¹H NMR(CDCl₃): δ 6.99 (t, 2H, J=8.7 Hz), 6.32 (dt, 1H, J=1.2 and 7.2 Hz),6.24-6.18 (m, 2H), 4.23 (q, 2H, J=7.2 Hz), 1.58 (s, 6H), 1.24 (t, 3H,J=6.9 Hz).

7.2.18 N-methyl-2-(5-amino-2-methylphenoxy)acetamide

In like manner to the preparation of ethyl 4-aminophenoxyacetate,hydrogenation of N-methyl-2-(2-methyl-5-nitrophenoxy)acetamide wascarried out to prepare N-methyl-2-(5-amino-2-methylphenoxy)acetamide. ¹HNMR (CD₃OD): δ 6.86 (d, 1H, J=7.5 Hz), 6.32-6.25 (m, 2H), 4.43 (s, 2H),2.82 (s, 3H), 2.14 (s, 3H).

7.2.19 6-Amino-2-(methoxycarbonyl)-(1H)-indole

6-Amino-2-(methoxycarbonyl)-(1H)-indole was prepared according to thefollowing references:

-   1. Adams, Richard E.; Press, Jeffery B.; Deegan, Edward G.;    Synthetic Communications (1991), 12 (5), 675-681.-   2. Boger, Dale L.; Yun, Weiya; Han, Nianhe; Johnson, Douglas S.;    Biiorganic & Medicinal Chemistry (1995), 3(6), 611-621

7.2.20 Preparation of 3-hydroxy-5-(methoxycarbonylmethyleneoxy)anilineand 3,5-bis(methoxycarbonylmethyleneoxy)aniline

Benzyl N-(3,5-dihydroxyphenyl)carbamate

To a mixture of 5-aminobenzene-1,3-diol (0.60 g, 3.7 mmole) and sodiumhydrogencarbonate (1.4 g, 16 mmole) in THF/water (15 mL, 1:1 v/v) wasadded dropwise benzyl chloroformate 1.6 mL, 11 mmole). After 3 h at rt,THF was removed under vacuum and the remaining aqueous layer wasextracted with ethyl acetate. Purification by column chromatograpy oversilica gel provided benzyl N-(3,5-dihydroxyphenyl)carbamate. ¹H NMR(CD₃OD): δ 7.42-7.25 (m, 5H), 6.46 (d, 2H, J=2.4 Hz), 5.97-5.94 (m, 1H),5.14 (s, 2H).

Benzyl N-[3-hydroxy-5-(methoxycarbonylmethyleneoxy) phenyl]carbamate andBenzyl N-[3,5-bis(methoxycarbonyl methyleneoxy)phenyl]carbamate

In like manner to the preparation of ethyl 4-nitrophenoxyacetate, benzylN-(3,5-dihydroxyphenyl)carbamate and methyl bromoacetate were reacted togive a mixture of benzylN-[3-hydroxy-5-(methoxycarbonylmethyleneoxy)phenyl]carbamate ¹H NMR(DMSO-d₆): δ 9.62 (s, 1H), 9.44 (s, 1H), 7.42-7.31 (m, 5H), 6.63 (s,1H), 6.50 (t, 1H, J=2.4 Hz), 5.93 (t, 1H, J=2.4 Hz), 5.10 (s, 2H), 4.63(s, 2H), 3.67 (s, 3H), and benzylN-[3,5-bis(methoxycarbonylmethyleneoxy)phenyl]carbamate ¹H NMR (CDCl₃):δ 7.38-7.32 (m, 5H), 6.86 (s, 1H), 6.67 (d, 2H, J=1.8 Hz), 6.19 (t, 1H,J=2.4 Hz), 5.16 (s, 2H), 4.57 (s, 4H), 3.78 (s, 6H)

which were separated by column chromatography over silica gel.

3-Hydroxy-5-(methoxycarbonylmethyleneoxy)aniline

In like manner to the preparation of ethyl 4-aminophenoxyacetate,hydrogenation of benzylN-[3-hydroxy-5-(methoxycarbonylmethyleneoxy)phenyl]carbamate was carriedout to prepare 3-hydroxy-5-(methoxycarbonylmethyleneoxy)aniline. ¹H NMR(CD₃OD): δ 5.87-5.80 (m, 2H), 5.78-5.72 (m, 1H), 4.56 (s, 2H), 3.76 (s,3H).

3,5-Bis(methoxycarbonylmethyleneoxy)aniline

In like manner to the preparation of ethyl 4-aminophenoxyacetate,hydrogenation of benzylN-[3,5-bis(methoxycarbonylmethyleneoxy)phenyl]carbamate was carried outto prepare 3,5-bis(methoxycarbonylmethyleneoxy)aniline. ¹H NMR (CD₃OD):δ 5.92 (d, 2H, J=2.4 Hz), 5.83 (t, 1H, J=2.4 Hz), 4.58 (s, 4H), 3.78 (s,6H).

7.2.21N4-(3,4-Ethylenedioxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R950287)

A solution of2-Chloro-5-ethoxycarbonyl-N4-(3,4-ethylenedioxyphenyl)-2,4-pyrimidineaminein EtOH was treated with a 25% aqueous solution of NH₃. The mixture wasstirred for 30 min at 100° C. and purified by flash chromatography onsilica gel to giveN4-(3,4-ethylenedioxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine as awhite solid. LCMS: purity: 92.3%; MS (m/e): 317.28 (MH⁺, 100).

7.2.22 Ethyl 6-Nitro-3-carboxy-4H-imidazo[5,1-c]-1,4-benzoxazine

Was prepared according to J. of Heterocyclic Chemistry, 26, 205, (1989)

7.2.23 Ethyl 6-Amino-3-carboxy-4H-imidazo[5,1-c]-1,4-benzoxazine

Ethyl 6-Nitro-3-carboxy-4H-imidazo[5,1-c]-1,4-benzoxazine was reducedshaken in MeOH under 40 p.s.i. H₂ with 20 weight percent of 10% Pd/C(Degussa) for 1 h then filtered and the solvent evaporated. The compoundwas purified directly by column chromatograph (EtOAc/hexane) to yieldEthyl 6-Amino-3-carboxy-4H-imidazo[5,1-c]-1,4-benzoxazine 1H (DMSO-d6)8.41 (s, 1H), 6.98 (m, 1H), 6.82 (m, 1H), 6.43 (m, 1H), 5.28 ((s, 2H),4.23 (q, 2H, J=6.2 Hz), 1.27 (t, 2H, J=6.2 Hz) purity 92% MS (m/e): 232(MH⁺).

7.2.24 6-Amino-3,3-dimethyl-1,4-benzoxazine

A mixture of 15 g 2-Amino-4-nitrophenol and 40 g Boc₂O in 300 mL CHCl₃was refluxed overnight filtered and the filtrate was evaporated to neardryness. The residue was triturated with hexanes, collected by suctionfiltration, and dried to yield 2-N-Boc-amino-4-nitrophenol. The2-N-Boc-amino-4-nitrophenol was refluxed in acetone with 15.6 mL of1-Chloro-2-methylpropene and 25 g potassium carbonate overnight. Thereaction mixture was poured into ice-slush, the solid was collected bysuction filtration and washed with water. The solid was dissolved inEtOAc and the organic was washed with 10% NaOH solution, water, thenbrine and dried over MgSO₄. The organic was filtered to remove thedrying agent and evaporated to yield 18 g1-(2-N-Boc-amino-4-nitrophenoxy)-2-methyl-2-propene. 7.8 g of1-(2-N-Boc-amino-4-nitrophenoxy)-2-methyl-2-propene was stirredovernight in methanolic HCl in a round-bottom flask with a septum wiredon, and then heated with a reflux condenser attached at 80° C. for 10minutes. The reaction was cooled and the methanol was removed byrotary-evaporation. The residue was dissolved in 30 mL of 4N HCl,transferred to a new vessel to leave behind any undissolved solids andcooled to 0° C. 1.83 g of NaNO₂ in 5 mL water was added drop wise andthe solution was neutralized with solid sodium bicarbonate. A solutionof 1.64 g NaN₃ in 17 mL water was added slowly drop wise and thereaction was stirred 30 minutes. The precipitate was collected bysuction filtration, washed well with water and dried on the funnel toyield 5.7 g 1-(2-Azido-4-nitrophenoxy)-2-methyl-2-propene. 7 g of1-(2-Azido-4-nitrophenoxy)-2-methyl-2-propene was refluxed in 300 mLbenzene overnight, cooled then evaporated. The crude product wasrecrystalized from EtOAc/Hexanes to yield3-Methyl-6-nitro-azirino[2,1-c]-1,4-benzoxazine in two crops with acombined mass of 5.1 1 g of3-Methyl-6-nitro-azirino[2,1-c]-1,4-benzoxazine was dissolved in 500 mLof MeOH/5% THF, 200 mg of 10% Pd/C (Degussa) was added and the resultingmixture was shaken under 30 p.s.i. H₂ atmosphere for 8 hours. Thereaction mixture was filtered through a pad of celite and the solventevaporated. The residue was dissolved in a minimum amount ofDCM/THF/MeOH and loaded onto a 5 cm by 20 cm 3% MeOH/DCM SiO₂ column andthe compound was eluted isocratically with a small amount of positivepressure. The appropriate fractions were combined and evaporated toyield 590 mg of 6-Amino-3,3-dimethyl-1,4-benzoxazine. 1H (DMSO-d6) 6.30(d, 1H), 5.75 (d, 1H), 5.65 (dd, 1H), 3.58 (s, 2H), 1.08 (s, 6H) purity99% MS (m/e): 179 (MH⁺).

7.2.25 Ethyl 4-Aminophenoxyacetate Ethyl 4-Nitrophenoxyacetate

A dry reaction flask equipped with a reflux condenser, N₂ inlet and amagnetic stirring bar was charged with 3-nitrophenol (76.45 g, 550mmol), K₂CO₃ (76.45 g, 550 mmol) and dry acetone (500 mL) under N₂atmosphere. To this at room temperature was added ethyl bromoacetate(55.44 mL, 500 mmol) over a period of 15 min. The reaction mixture wasrefluxed for 16 h, cooled and poured over ice-water (4 Kg). Theresulting aqueous solution was extracted with CH₂Cl₂ (3×500 mL), driedover anhydrous Na₂SO₄ and solvent was removed to obtain 103 g (92%) ofthe desired ethyl 4-nitrophenoxyacetate. ¹H NMR (CDCl₃): δ 8.20 (d, 2H,J=8.2 Hz), 6.95 (d, 2H, J=8.1 Hz), 4.72 (s, 2H), 4.25 (q, 2H), 1.23 (t,3H); LCMS: ret. time: 27.07 min.; purity: 100%; MS: 267(M+acetonitrile).

Ethyl 4-Aminophenoxyacetate

A solution of ethyl 4-nitrophenoxyacetate (15 g) in EtOH (400 mL) washydrogenated at 40 PSI for 40 minutes in the presence of 10% Pd/C (1.5g, 10% by weight). After the filtration through a celite the solvent wasremoved under a reduced pressure to obtain ethyl 4-aminophenoxyacetate.¹H NMR (CDCl₃): δ 6.77 (d, 2H, 8.1 Hz), 6.60 (d, 2H, J=8.0 Hz), 4.50 (s,2H), 4.24 (q, 2H), 1.24 (t, 3H); LCMS: ret. time: 12.00 min.; purity:100%; MS (m/e): 196 (MH⁺).

7.2.26 tert-Butyl 4-Aminophenoxyacetate tert-Butyl 4-Nitrophenoxyacetate

In like manner to the preparation of ethyl 4-nitrophenoxyacetate,4-nitrophenol and tert-butyl bromoacetate were reacted to preparetert-butyl 4-nitrophenoxyacetate. ¹H NMR (CDCl₃): δ 8.2 (d, 2H, J=8.1Hz), 6.95 (d, 2H, J=8.2 Hz), 4.60 (s, 2H), 1.42 (s, 9H).

tert-Butyl 4-Aminophenoxyacetate

In like manner to the preparation of ethyl 4-aminophenoxyacetate,hydrogenation of tert-butyl 4-nitrophenoxyacetate was carried out toprepare tert-butyl 4-aminophenoxyacetate. ¹H NMR (CDCl₃): δ 6.74 (d, 2H,J=9 Hz), 6.62 (d, 2H, J=9 Hz), 4.42 (s, 2H), 1.42 (s, 9H); LCMS: ret.time: 16.35 min.; purity: 94%; MS (m/e): 224 (MH⁺).

7.2.27 Ethyl 3-Aminophenoxyacetate Ethyl 3-Nitrophenoxyacetate

In like manner to the preparation of ethyl 4-nitrophenoxyacetate,3-nitrophenol and ethyl bromoacetate were reacted to prepare ethyl3-nitrophenoxyacetate. ¹H NMR (CDCl₃): δ 7.88 (dt, 1H, J=1.2 and 8.7Hz), 7.71 (t, 1H, J=2.4 Hz), 7.45 (t, 1H, J=8.4 Hz), 7.27 (dt, 1H, J=2.4and 8.4 Hz), 4.70 (s, 2H), 4.29 (q, 2H, J=6.9 Hz), 1.30 (t, 3H, J=6.9Hz); LCMS: ret. time: 27.28 min.; purity: 96%.

Ethyl 3-Aminophenoxyacetate

In like manner to the preparation of ethyl 4-aminophenoxyacetate,hydrogenation of ethyl 3-nitrophenoxyacetate was carried out to prepareethyl 3-aminophenoxyacetate. ¹H NMR (CDCl₃): δ 7.05 (t, 1H, J=7.2 Hz),6.30 (m, 3H), 4.56 (s, 2H), 4.25 (q, 2H, J=7.2 Hz), 1.29 (t, 3H, J=6.9Hz); LCMS: ret. time: 10.69 min.; purity: 96%; MS (m/e): 196 (MH⁺).

7.2.28 (+)-Ethyl 2-(4-Aminophenoxy)propionate

In like manner to the preparation of ethyl 4-aminophenoxyacetate,hydrogenation of ethyl (+)-2-(4-nitrophenoxy)propionate was carried outto prepare (+) ethyl 2-(4-aminophenoxy)propionate. ¹H NMR (CDCl₃): δ6.70 (d, 2H), 6.58 (d, 2H), 4.60 (m, 1H), 4.20 (q, 2H), 3.2 (bs, 2H),1.45 (d, 3H), 1.22 (t, 3H).

7.2.29 N-Methyl 3-Aminophenoxyacetamide N-Methyl 3-Nitrophenoxyacetamide

A mixture of ethyl 3-nitrophenoxyacetate (9.12 g, 40 mmol), methylaminehydrochloride (26.8 g, 400 mmol) and diisopropylethylamine (35.5 mL, 200mL) in MeOH (100 mL) was stirred in a pressure vial at 90° C. for 6 h.The reaction was cooled to room temperature, diluted with water (1liter), the solid formed was filtered, washed with water and dried toget the desired N-methyl 3-nitrophenoxyacetamide (8 g, 95%). ¹H NMRCDCl₃): δ 7.91 (dd, 1H, J=1.8 and 8.1 Hz), 7.78 (t, 1H, J=2.4 Hz), 7.50(t, 1H, J=8.7 Hz), 7.29 (dd, 1H, J=1.8 and 8.4 Hz), 6.50 (bs, 2H), 4.57(s, 2H), 2.95 and 2.93 (2s, 3H); LCMS: ret. time: 17.54 min.; purity:100%; MS (m/e): 211 (MH⁺).

N-Methyl 3-Aminophenoxyacetamide

In like manner to the preparation of ethyl 4-aminophenoxyacetate, thehydrogenation of N-methyl 3-nitrophenoxyacetamide (8 g, 39 mmol) wasconducted to give the desired N-methyl 3-aminophenoxyacetamide (6 g,86%). ¹H NMR (CD₃OD): δ 6.99 (t, 1H, J=8.1 Hz), 6.37-6.25 (m, 3H), 4.41(s, 2H), 2.80 (s, 3H); LCMS: ret. time: 19.80 min.; purity: 100%.

7.2.30 2-Methoxycarbonyl-5-aminobenzofuran (R926610)2-Methoxycarbonyl-5-nitrobenzofuran (R926609)

To a suspension of 5-nitro-2-benzofurancarboxylic acid (5 g, 24.15 mmol)in CH₂Cl₂ (250 mL) at 0° C. was added DMF (0.100 mL) followed by (COCl)₂(2M in CH₂Cl₂, 36.23 mL, 72.46 mL) over a period of 10 min. The reactionwas stirred at 0° C. for 1 h and then at room temperature for 30 min.The reaction solvent was removed under a reduced pressure, dried underhigh vacuum and again suspended in CH₂Cl₂ (250 mL). The solution wascooled to 0° C., were added pyridine (4.8 mL, 48.03 mmol) followed byMeOH (10 mL, excess) and stirred overnight. The extractive work-up withCH₂Cl₂ gave the expected 2-methoxycarbonyl-5-nitrobenzofuran (R926609).¹H NMR (CDCl₃): δ 8.66 (d, 1H, J=2.4 Hz), 8.36 (dd, 1H, J=2.4 and 9.6Hz), 7.71 (d, 1H, J=9.3 Hz), 7.65 (s, 1H), 4.01 (s, 3H); LCMS: ret.time: 26.94 min.

2-Methoxycarbonyl-5-aminobenzofuran (R926610)

In like manner to the preparation of ethyl 4-aminophenoxyacetate, thehydrogenation of 2-methoxycarbonyl-5-nitrobenzofuran (2 g) in MeOH gave2-methoxycarbonyl-5-aminobenzofuran. ¹H NMR (CDCl₃): δ 7.38 (bt, 2H),6.90 (bd, 1H), 6.85 (bdd, 1H), 3.98 (s, 3H).

7.2.31 Methyl 2-(2-methyl-5-nitrophenoxy)acetate

In like manner to the preparation of ethyl 4-nitrophenoxyacetate,2-methyl-5-nitrophenol and methyl bromoacetate were reacted to preparemethyl 2-(2-methyl-5-nitrophenoxy)acetate. 1H NMR (CD₃OD): δ 7.80 (dd,1H, J=2.4 and 8.1 Hz), 7.65 (d, 1H, J=2.4 Hz), 7.38 (d, 1H, J=8.1 Hz),4.90 (s, 2H), 3.80 (s, 3H), 2.36 (s, 3H).

7.2.32 Ethyl 2-methyl-2-(3-nitrophenoxy)propanate

A mixture of 3-nitrophenol (0.50 g, 3.6 mmole), ethylbromodimethylacetate (0.64 g, 3.3 mmole), K₂CO₃ (1.3 g, 9.4 mmole),potassium iodide (catalytic) in absolute ethanol (8 mL) was heated at70° C. for 18 h. The reaction mixture was cooled, poured into asaturated solution of NaHCO₃, and extracted with dichloromethane. Theproduct, ethyl 2-methyl-2-(3-nitrophenoxy)propanate, was obtained afterpurification by column chromatography over silica gel. ¹H NMR (CDCl₃): δ7.85 (dt, 1H, J=1.2 and 8.1 Hz), 7.68 (t, 1H, J=2.4 Hz), 7.40 (t, 1H,J=8.4 Hz), 7.19-7.13 (m, 1H), 4.26 (q, 2H, J=7.2 Hz), 1.64 (s, 6H), 1.26(t, 3H, J=7.21),

7.2.33 N-Methyl-2-(2-methyl-5-nitrophenoxy)acetamide

In like manner to the preparation of N-methyl 3-nitrophenoxyacetamide,methyl 2-methyl-5-nitrophenoxyacetate and methylamine hydrochloride werereacted to prepare N-methyl-2-(2-methyl-5-nitrophenoxy)acetamide. ¹H NMR(CD₃OD): δ 7.82 (dd, 1H, J=2.4 and 8.1 Hz), 7.69 (d, 1H, J=2.4 Hz), 7.40(d, 1H, J=8.1 Hz), 4.66 (s, 2H), 2.83 (s, 3H), 2.40 (s, 3H).

7.2.34 N,2-Dimethyl-2-(3-nitrophenoxy)propanamide

In like manner to the preparation of ethyl2-methyl-2-(3-nitrophenoxy)propanate, 3-nitrophenol andN,2-dimethyl-2-bromopropanamide (prepared according to the followingreference: Guziec, Frank S., Jr.; Torres, Felix F. Journal of OrganicChemistry (1993), 58(6), 1604-6) were reacted to prepareN,2-dimethyl-2-(3-nitrophenoxy)propanamide. ¹H NMR (CDCl₃): δ 7.94 (dt,1H, J=1.2 and 8.1 Hz), 7.78 (t, 1H, J=2.4 Hz), 7.45 (t, 1H, J=8.4 Hz),7.22 (ddd, 1H, J=1.2, 2.4, and 8.1 Hz), 6.61 (bs, 1H), 2.89 (d, 3H,J=5.1 Hz), 1.55 (s, 6H).

7.2.35 4-Amino-[(1H,1,2,3,4-tetrazolyl)methyleneoxy]benzene4-Nitro-[(1H, 1,2,3,4-tetrazol-5-yl)methyleneoxy]benzene

A mixture of 2-cyanomethoxy-4-nitrophenyl (5.8 g, 32.6 mmol), sodiumazide (6.3 g, 98.0 mmol) and ammonium chloride (8.5 g, 163.3 mmol) wassuspended in DMF (100 mL) containing acetic acid (1 mL) and the mixtureheated at 70° C. After 17 h, the reaction was cooled to room temperatureand 2 N aqueous hydrochloric acid (100 mL) was added. The solid whichprecipitated out of the reaction mixture was collected by filtration,washed with water (2×20 mL) then hexane (30 mL), affording compound4-nitro-[(1H, 1,2,3,4-tetrazol-5-yl)methyleneoxy]benzene (6.7 g, 99%) asan orange solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.25 (d, J=9.2 Hz, 2H),7.29 (d, J=9.1 Hz, 2H), 5.68 (s, 2H); ESI MS m/z 220 [C₈H₇N₅O₃—H]⁻.

4-Amino-[(1H,1,2,3,4-tetrazolyl)methyleneoxy]benzene

A mixture of 4-nitro-[(1,2,3,4-tetrazol-5-yl)methyleneoxy]benzene (6.7g, 30.4 mmol) and 5 wt % palladium on carbon (700 mg) suspended inethanol/concentrated hydrochloric acid (14:1, 150 mL) was hydrogenatedin a sealed vessel at 50 psi. The mixture was shaken until no furtherhydrogen uptake was observed, after which the reaction was filteredthrough diatomaccous earth with chloroform and the filtrate concentratedto afford crude product.

Purification by flash chromatography (7:2.5:0.5 CHCl₃/CH₃OH/NH₄OH)afforded 4-amino-[(1H, 1,2,3,4-tetrazolyl)methyleneoxy)]benzene as abrown solid: ¹H NMR (300 MHz, DMSO-d₆) δ 6.76 (d, J=8.7 Hz, 2H), 6.52(d, J=8.7 Hz, 2H), 5.07 (s, 2H); ESI MS m/z 190 [C₈H₉N₅O—H]⁻.

7.2.36 4-Amino-[(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene4-Nitro-[(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene and4-Nitro-[(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]benzene

A mixture of 4-nitro-[(1H, 1,2,3,4-tetrazolyl)methyleneoxy]benzene(10.00 g, 45.2 mmol), cesium carbonate (22.09 g, 67.8 mmol) and methyliodide (7.70 g, 54.3 mmol) in DMF (200 mL) was stirred at roomtemperature for 24 h. The reaction mixture was concentrated to removemost of the DMF and the crude residue was partitioned between chloroform(100 mL) and water (50 mL). The organic phase was separated, washed withbrine, dried (Na₂SO₄) and concentrated to afford crude product as aorange solid. Purification by flash chromatography (chloroform) afforded4-nitro-[(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene: ¹H NMR(300 MHz, DMSO-d₆) δ 8.26 (d, J=9.2 Hz, 2H), 7.31 (d, J=9.2 Hz, 2H),5.72 (s, 2H), 4.15 (s, 3H); and4-nitro-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]benzene: ¹H NMR(300 MHz, DMSO-d₆) δ 8.24 (d, J=9.3 Hz, 2H), 7.29 (d, J=9.3 Hz, 2H),5.58 (s, 2H), 4.41 (s, 3H).

4-Amino-[(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene

A mixture of4-nitro-[(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene (3.60 g,15.3 mmol) and 5% Pd/C (0.40 g) in 14:1 ethanol/concentratedhydrochloric acid (75 mL) was shaken at room temperature in a atmosphereof hydrogen at 50 psi. After 4 h no further hydrogen uptake wasobserved. The reaction mixture was filtered through diatomaceous earth,the solids washed with a 6:3:1 chloroform/methanol/concentrated ammoniumhydroxide solution and the filtrate concentrated to afford crude4-amino-[(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene, whichwas purified by flash chromatography (95:5 chloroform/methanol): ¹H NMR(300 MHz, DMSO-d₆) δ 7.48 (br s, 2H), 6.79 (d, J=6.9 Hz, 2H), 6.55 (d,J=6.9 Hz, 2H), 5.36 (s, 2H), 4.10 (s, 3H).

7.2.37 4-Amino-[(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]benzene

A mixture of4-nitro-[(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]benzene (3.60 g,15.3 mmol) and 5% Pd/C (0.40 g) in 14:1 ethanol/concentratedhydrochloric acid (75 mL) was shaken at room temperature in a hydrogenatmosphere at 50 psi. After 3 h no further hydrogen uptake was observed.The reaction mixture was filtered through diatomaceous earth, the solidswashed with a 6:3:1 chloroform/methanol/concentrated ammonium hydroxidesolution and the filtrate concentrated to afford crude4-amino-[(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]benzene, which waspurified by flash chromatography (95:5 chloroform/methanol): ¹H NMR (300MHz, DMSO-d₆) δ 6.80 (br s, 2H), 6.75 (d, J=9.0 Hz, 2H), 6.50 (d, J=9.0Hz, 2H), 5.17 (s, 2H), 4.37 (s, 3H).

7.2.38 2-Ethoxycarbonyl-5-aminoindole (R926611)

In like manner to the preparation of ethyl 4-aminophenoxyacetate, thehydrogenation of 2-ethoxycarbonyl-5-nitroindole gave the2-ethoxycarbonyl-5-aminoindol. LCMS: ret. time: 13.44 min.; purity: 93%;MS (m/e): 205 (MH⁺).

7.2.39 5-[(4-Aminophenoxy)methyl]-3-phenyl-1,2,4-oaxadiazole

Preparation of 5-[4-(Nitrophenoxy)methyl]-3-phenyl-1,2,4-oxadiazole

4-Nitrophenol (0.36 g, 2.56 mmole),5-(chloromethyl)-3-phenyl-1,2,4-oxadiazole (0.5 g, 2.56 mmole) andanhydrous K₂CO₃ (0.39 g, 2.82 mmole) were dissolved in anhydrous acetone(20 mL) and heated to reflux for 12 h. Reaction mixture was cooled andthe solvent removed under vacuum. The crude solid formed was collectedby filtration, washed with water and dried under vacuum to provide5-[(4-nitrophenoxy)methyl]-3-phenyl-1,2,4-oxadiazole (0.70 g, 92%). ¹HNMR (CDCl₃): δ 8.25 (d, 2H, J=8.8 Hz), 8.08 (dd, 2H, J=8.2 Hz),7.52-7.49 (m, 3H), 7.13 (d, 2H, J=8.8 Hz), 5.45 (s, 2H).

Preparation of 5-[(4-Aminophenoxy)methyl]-3-phenyl-1,2,4-oxadiazole

The 5-[(4-nitrophenoxy)methyl]-3-phenyl-1,2,4-oxadiazole (0.5 g, 1.68mmole) was dissolved in methanol:methylenechloride (1:1) (120 mL).Aqueous solution of (15 mL) sodium hydrosulfite (0.88 g, 5.05 mmole) andK₂CO₃ (0.70 g, 5.06 mmole) was added dropwise under nitrogen for 10 min.The contents were allowed to stir at room temperature. After consumptionof starting material, reaction mixture was concentrated, diluted withwater till the homogeneous layer formed. The aqueous layer was extractedwith several times with ethylacetate and methylene chloride. The turbidorganic layers were combined, dried with anhydrous Na₂SO₄ andconcentrated. Purification of the solid concentrate by silica gelchromatography provided5-[(4-aminophenoxy)methyl]-3-phenyl-1,2,4-oxadiazole (0.23 g, 51%). ¹HNMR (CDCl₃): δ 8.11 (m, 2H), 7.52-7.46 (m, 3H), 6.87 (d, 2H, J=8.8 Hz),6.64 (d, 2H, J=8.8 Hz), 5.26 (s, 2H), 3.49 (br s, 2H).

Preparation of 5-[(4-Nitrophenoxy)methyl]-3-methyl-1,2,4-oxadiazole

A mixture of 4-nitrophenoxy acetic acid (2.25 g, 11.4 mmole),acetamideoxime, triethylamine hydrochloride (3.85 g, 27.62 mmole),EDCI.HCl (4.37 g, 22.79 mmole) and diisopropylethylamine (7.42 g, 57.40mmole) in anhydrous THF (250 ml) was refluxed for 18 h. The unhomogenousbrown colored reaction mixture was quenched with water and extractedwith EtOAc (3×300 mL). The combined organic layers washed successivelywith aqueous NaHCO₃, brine and dried over anhydrous Na₂SO₄. Removal ofsolvent and purified by chromatographic purification provided5-[(4-nitrophenoxy)methyl]-3-methyl-1,2,4-oxadiazole (1.62 g, 60%). ¹HNMR (CDCl₃): δ 8.24 (d, 2H, J=8.8 Hz), 7.08 (d, 2H, J=8.8 Hz), 5.36 (s,2H), 2.44 (s, 3H).

Preparation of 5-[(4-Aminophenoxy)methyl]-3-methyl-1,2,4-oxadiazole

In like manner to the preparation of5-[(4-aminophenoxy)methyl]-3-phenyl-1,2,4-oxadiazole,5-(4-nitrophenoxymethyl)-3-methyl-1,2,4-oxadiazole was reacted withaqueous solution of sodium hydrosulfite and K₂CO₃ to prepare5-[(4-aminophenox)ymethyl]-3-methyl-1,2,4-oxadiazole. ¹H NMR (CDCl₃): δ6.82 (d, 2H, J=8.8 Hz), 6.63 (d, 2H, J=8.8 Hz), 5.15 (s, 2H), 3.38 (brs, 2H), 2.41 (s, 3H).

7.2.40 Ethyl 2-(4-aminophenyl)-2-methylpropionate

Ethyl 2-methyl-2-(4-nitrophenyl)propionate

A dry reaction flask charged with ethyl 4-nitrophenylacetate (5.0 g,23.89 mmole), iodomethane (8.48 g, 3.72 mL, 59.74 mmole), 18-crown-6(1.57 g, 5.93 mmole) in dry THF (200 mL) was cooled to −78° C. undernitrogen atmosphere. While stirring the contents, t-BuOK (5.90 g, 52.57mmole) was added portionwise. The resulting violet precipitate wasstirred at −78 OC for 2 h and allowed the contents to warm to roomtemperature. The reaction was stirred at room temperature for 6 h. Atthis time, once again the contents were cooled to −78° C. anotherportion of iodomethane, t-BuOK, and 18-crown-6 were added successivelyand stirred at the same temperature for 2 h. The reaction was allowed towarm to room temperature and stirred overnight. The reaction wasquenched with saturated aq. NH₄Cl (75 mL), the resulting homogenousmixture extracted with ether (4×200 mL), dried over anhydrous Na₂SO₄,and concentrated. The concentrate was purified by silica gel columnchromatography with 1% EtOAc/hexanes to provide ethyl2-methyl-2-(4-nitrophenyl)propionate as a pale yellow oil (2.38, 42%).¹H NMR (CDCl₃): δ 8.17 (d, 2H, J=8.8 Hz), 7.49 (d, 2H, J=8.8 Hz), 4.12(qt, 2H, J=7.0 Hz), 1.60 (s, 6H), 1.17 (t, 3H, J=7.0 Hz).

Ethyl-2-(4-aminophenyl)-2-methylpropionate

In like manner to the preparation of ethyl 4-aminophenoxyacetate, thehydrogenation of ethyl 2-methyl-2-(4-nitrophenyl)propionate providedethyl-2-(4-aminophenyl)-2-methylpropionate. ¹H NMR (CDCl₃): δ 7.16 (d,2H, J=8.8 Hz), 6.63 (d, 2H, J=8.8 Hz), 4.09 (qt, 2H, J=7.0 Hz), 3.62 (brs, 2H), 1.52 (s, 6H), 1.17 (t, 3H, J=7.0 Hz).

7.2.41 Anilines Substituted with 1,3,4-oxadiazole Moieties

N′1-(3-Chlorobenzoyl)-3-nitrobenzene-1-carbohydrazide

To a solution of 3-chlorobenzohydrazide (1 equivalent) and pyridine (2equivalents) in CH₂Cl₂ at 0° C. was added a CH₂Cl₂ solution of3-nitrobenzoyl chloride (1 equivalents) and stirred at 0° C. for 1 h andthen at room temperature for overnight. The resulting solution wasconcentrated and diluted with water, basified with NaHCO₃, the solid wasfiltered, washed with water, dried and analyzed to obtainN′1-(3-chlorobenzoyl)-3-nitrobenzene-1-carbohydrazide. ¹H NMR (DMSO-d6):δ 10.99 (s, 1H), 10.79 (s, 1H), 8.73 (bs, 1H), 8.43 (bdd, 1H, J=1.2 and8.1 Hz), 8.33 (bdd, 1J, J=8.4 Hz), 7.95 (s, 1H), 7.87 (m, 2H), 7.67(bdd, 1H, J=1.2 and 8.1 Hz), 7.57 (t, 1H, J=7.8 Hz); LCMS: purity: 85%;MS (m/e): 320 (MH⁺).

[2-(3-Chlorophenyl)-1,3,4-oxadiazol-5-yl]-3-nitrobenzene

A suspension of N′1-(3-chlorobenzoyl)-3-nitrobenzene-1-carbohydrazide(0.321 g) in POCl₃ (3 mL) was stirred at 90° C. for 24 h. The resultingclear solution was quenched with ice-water, solid obtained was filteredwashed with water, dried and analyzed to give[2-(3-chlorophenyl)-1,3,4-oxadiazol-5-yl]-3-nitrobenzene. ¹H NMR(DMSO-d6): δ 8.86 (t, 1H, J=1.8 Hz), 8.59 (dt, 1H, J=1.8 and 8.4 Hz),8.48 (m, 1H), 8.25 (t, 1H, J=1.8 Hz), 8.16 (dt, 1H, J=1.2 and 7.5 Hz),7.93 (t, 1H, J=8.1 Hz), 7.75 (m, 1H), 7.66 (t, 1H, J=7.5 Hz), LCMS:purity: 86%; MS (m/e): 302 (MH⁺).

Reduction of [2-(3-chlorophenyl)-1,3,4-oxadiazol-5-yl]-3-nitrobenzene

The hydrogenation of[2-(3-chlorophenyl)-1,3,4-oxadiazol-5-yl]-3-nitrobenzene (0.2 g) using10% Pd/C (0.04 g) in MeOH (200 mL) at 15 PSI for 1 h gave a mixture oftwo products viz.3-amino-[2-(3-chlorophenyl)-1,3,4-oxadiazol-5-yl]benzene and3-amino-(2-phenyl-1,3,4-oxadiazol-5-yl)benzene which were separated bysilica gel column chromatography using n-hexanes then n-hexanes: 5-10%EtOAc as a solvent system.3-Amino-[2-(3-chlorophenyl)-1,3,4-oxadiazol-5-yl]benzene: ¹H NMR(DMSO-d6): δ 8.08 (m, 2H), 7.64 (m, 4H), 7.42 (m, 1H), 7.10 (m, 1H);LCMS: purity: 82%; MS (m/e): 272 (MH⁺).3-Amino-(2-phenyl-1,3,4-oxadiazol-5-yl)benzene: ¹H NMR (DMSO-d6): δ 8.13(m, 1H), 7.54 (m, 5H), 7.30 (m, 1H), 6.86 (dd, 1H, J=1.5 and 8.1 Hz);LCMS: purity: 93%; MS (m/e): 238 (MH⁺).

N′1-(Ethoxycarbonylmethylenecabonyl)-3-nitrobenzene-1-carbohydrazide

In like manner to the preparation ofN′1-(3-chlorobenzoyl)-3-nitrobenzene-1-carbohydrazide, the reaction of3-nitrobenzoyl chloride with ethoxycarbonylmethlenecarbohydrazide gaveN′1-(ethoxycarbonylmethylenecabonyl)-3-nitrobenzene-1-carbohydrazide. ¹HNMR (CD₃OD): δ 8.74 (m, 1H), 8.44 (dd, 1H, 1.8 and 8.1 Hz), 8.25 (bd,1H, J=8.4 Hz), 7.76 (t, 1H, J=8.4 Hz), 4.22 (q, 2H, J=6.9 Hz), 3.44 (bs,2H), 1.29 (t, 3H, J=6.8 Hz); LCMS: purity: 93%; MS (m/e): 296 (MH⁺).

[2-(Ethoxycarbonylmethylene)-1,3,4-oxadiazol-5-yl]-3-nitrobenzene

In like manner to the preparation of[2-(3-chlorophenyl)-1,3,4-oxadiazol-5-yl]-3-nitrobenzene the reaction ofPOCl₃ withN′1-(ethoxycarbonylmethylenecabonyl)-3-nitrobenzene-1-carbohydrazidegave [2-(ethoxycarbonylmethylene)-1,3,4-oxadiazol-5-yl]-3-nitrobenzene.¹H NMR (CDCl₃): δ 8.88 (t, 1H, J=1.8 Hz), 8.42 (m, 2H), 7.74 (t, 1H,J=7.5 Hz), 4.27 (q, 2H, J=7.2 Hz), 4.08 (s, 2H), 1.31 (t, 3H, J=7.2 Hz);LCMS: purity: 95%; MS (m/e): 278 (MH⁺).

7.2.42 Synthesis of(±)-5-Amino-(2,3-dihydro-2-methoxycarbonyl)benzofuran

2-Methoxycarbonyl-5-nitrobenzofuran

A mixture of 2-carboxy-5-nitrobenzofuran (2.0 g), MeOH (10 mL) andConcentrated H₂SO₄ (2.1 mL) was heated in a sealed tube at 60° C. for 3h. Upon cooling to the room temperature it was quenched with ice-waterand carefully basified with addition of NaHCO₃. The solid obtained wasfiltered, washed with water, dried and analyzed to give2-methoxycarbonyl-5-nitrobenzofuran. ¹H NMR (CDCl₃): δ 8.66 (d, 1H,J=2.4 Hz), 8.36 (dd, 1H, J=2.4 and 9.6 Hz), 7.71 (d, 1H, J=9.3 Hz), 7.65(s, 1H), 4.01 (s, 3H); LCMS: purity: 97%; MS (m/e): 222 (MH⁺).

(±)-5-Amino-(2,3-dihydro-2-methoxycarbonyl)benzofuran

A suspension of 2-methoxycarbonyl-5-nitrobenzofuran (2.0 g), 10% Pd/C(2.0 g), Na₂SO₄ (2.0 g) in MeOH (500 mL) was hydrogenated at 55 PSI for3 days. The resulting solution was filtered through a pad of celite,concentrated and chromatographed using n-hexanes then 10%, 20%EtOAc/n-hexanes to give(±)-5-amino-(2,3-dihydro-2-methoxycarbonyl)benzofuran. ¹H NMR (CDCl₃): δ6.69 (d, 1H, J=8.1 Hz), 6.56 (d, 1H, J=1.2 Hz), 6.48 (dd, 1H, J=1.8 and7.5 Hz), 5.14 (dd, 1H, J=6.6 and 7.2 Hz), 3.79 (s, 3H), 3.47 (dd, 1H,J=10.5 and 10.8 Hz), 3.26 (dd, 1H, J=7.2 and 6.6 Hz); LCMS: purity:100%; MS (m/e): 194 (MH⁺).

7.2.43 3-[1-Bis(ethoxycarbonyl)ethoxy]aniline Preparation of Diethyl2-methyl-2-(3-nitrophenoxy)malonate

Diethyl 2-bromo-2-methylmalonate (1.0 g, 3.95 mmole) was added to astirred suspension of potassium fluoride (0.57 g, 9.8 mmole) in dry DMF(5 mL). After stirring for 20 min at room temperature, 3-nitrophenol(0.55 g, 3.95 mmole) was added. The resulting mixture was stirred at 60°C. for 6 h, cooled to room temperature, diluted with water (30 mL) andextracted with ethyl acetate (3×200 mL). The organic layer was washedwith aq. 1N NaOH (2×75 mL), dried over anhydrous Na₂SO₄, filtered andevaporated in vacuo to provide diethyl2-methyl-2-(3-nitrophenoxy)malonate (0.89 g, 80%). ¹H NMR (CDCl₃): δ7.92 (dd, 1H, J=2.3 and 8.2 Hz), 7.82 (t, 1H, J=2.3 Hz), 7.41 (t, 1H,J=8.2 Hz), 7.30 (dd, 1H, J=2.3 and 8.2 Hz), 4.28 (qt, 4H, J=7.0 Hz),1.81 (s, 3H), 1.26 (t, 6H, J=7.0 Hz).

Preparation of 3-[1-Bis(ethoxycarbonyl)ethoxy]aniline

Diethyl 2-methyl-2-(3-nitrophenoxy)malonate (0.75 g, 2.40 mmole) wasdissolved in toluene: ethanol (1:1, 100 mL), transferred to par shakerbottle containing Pd/C (0.15 g) and anhydrous Na₂SO₄ (5.0 g) in thepresence of nitrogen atmosphere. The resulting mixture was treated withhydrogen (30 PSI) till the disappearance of diethyl2-methyl-2-(3-nitrophenoxy)malonate (2 h). The mixture was filteredthrough celite covered with anhydrous Na₂SO₄ followed by washing thecelite pad with EtOAc. The filtrated was concentrated and dried undervacuo to furnish 3-[1-bis(ethoxycarbonyl)ethoxy]aniline in quantitativeyield. ¹H NMR (CDCl₃): δ 6.98 (t, 1H, J=8.2 Hz), 6.37-6.28 (m, 3H), 4.26(qt, 4H, J=7.0 Hz), 3.65 (br s, 2H), 1.72 (s, 3H), 1.24 (t, 6H, J=7.0Hz).

7.2.44 Preparation of 4-(4-aminophenoxymethyl)-2-methoxycarbonyl-furan

Preparation of 4-(4-nitrophenoxymethyl)-2-methoxycarbonyl-furan

3-Nitrophenol (1.0 g, 7.19 mmole), methyl 5-(chloromethyl)-2-furoate(1.38 g, 7.90 mmole) and anhydrous K₂CO₃ (1.19 g, 8.60 mmole) in acetone(30 mL) were refluxed for 8 h.

The reaction mixture was cooled and diluted with water. The resultantwhite solid was filtered, washed with water and air dried overnight togive 1.81 g (90%) of the desired product. ¹H NMR (CDCl₃): δ 7.86 (dd,1H, J=2.3 and 8.2 Hz), 7.80 (t, 1H, J=2.3 Hz), 7.45 (t, 1H, J=8.2 Hz),7.27 (dd, 1H, J=2.3 and 8.2 Hz), 7.17 (d, 1H, J=3.5 Hz), 6.58 (d, 1H,J=3.5 Hz), 5.13 (s, 2H), 3.90 (s, 3H).

Preparation of 4-(4-aminophenoxymethyl)-2-methoxycarbonyl-furan

In like manner to the reduction of diethyl2-methyl-2-(3-nitrophenoxy)malonate,4-(4-nitrophenoxymethyl)-2-methoxycarbonyl-furan was reduced to provide4-(4-aminophenoxymethyl)-2-methoxycarbonyl-furan. ¹H NMR (CDCl₃): δ 7.15(d, 1H, J=3.5 Hz), 7.05 (t, 1H, J=8.2 Hz), 6.50 (d, 1H, J=3.5 Hz),6.37-6.27 (m, 3H), 5.01 (s, 2H), 3.89 (s, 3H).

7.2.45 Preparation of 6-amino-1-(methoxycarbonyl)methylindazoline

Preparation of 1-(methoxycarbonyl)methyl-6-nitroindazoline

To a solution of 6-nitroindazoline (2.0 g, 12.25 mmole) in dry DMF wasadded anhydrous K₂CO₃ (1.84 g, 13.31 mmole) and methyl 2-bromoacetate(2.04 g, 13.33 mmole). The resulting mixture was stirred at roomtemperature for 12 h. The reaction mixture was quenched with water andthe resulting solid was collected by filtration, washed with excessivewater, and air dried. The yellow solid collected was purified by silicagel column chromatography using gradient solvent system to furnish twoproducts. The desired product (1.12 g, 41%) with high R/value on the TLCin 30% EtOAc:hexanes was collected.

In like manner to the reduction of diethyl2-methyl-2-(3-nitrophenoxy)malonate,1-(Methoxycarbonyl)methyl-6-nitro-indazoline was reduced to provide6-amino-1-(methoxycarbonyl)methylindazoline. ¹H NMR (CDCl₃): δ 7.73 (d,1H, J=1.1 Hz), 7.35 (d, 1H, J=8.2 Hz), 6.49 (dd, 1H, J=1.8 and 8.8 Hz),6.39 (s, 1H), 5.34 (br s, 2H), 5.10 (s, 2H), 3.64 (s, 3H).

Preparation of 1-(methoxycarbonyl)methyl-5-nitroindazoline

In like manner to the preparation of1-(methoxycarbonyl)methyl-6-nitroindazoline,1-(methoxycarbonyl)methyl-5-nitroindazoline was prepared by alkylationof 5-nitroindazoline with methyl 2-bromoacetate in presence of K₂CO₃.The desired product (1.34 g, 46%) with high R_(f) value on the TLC in30% EtOAc:hexanes was collected by silica gel column chromatographicpurification. ¹H NMR (CDCl₃): δ 8.75 (d, 1H, J=1.8 Hz), 8.30 (dd, 1H,J=2.3 and 8.2 Hz), 8.26 (s, 1H), 7.40 (d, 1H, J=8.2 Hz), 5.22 (s, 2H),3.78 (s, 3H).

Preparation of 5-amino-1-(methoxycarbonyl)methylindazoline

In like manner to the reduction of diethyl2-methyl-2-(3-nitrophenoxy)malonate,1-(Methoxycarbonyl)methyl-5-nitro-indazoline was reduced to provide5-amino-1-(methoxycarbonyl)methylindazoline. ¹H NMR (CDCl₃): δ 7.84 (d,1H, J=2.3 Hz), 7.15 (d, 1H, J=8.8 Hz), 6.95 (d, 1H, J=2.3 Hz), 6.88 (dd,1H, J=2.3 and 8.8 Hz), 5.09 (s, 2H), 3.73 (s, 3H).

Preparation of 1-(2-ethoxycarbonylethyl)-6-nitroindazoline

In like manner to the preparation of1-(methoxycarbonyl)methyl-6-nitroindazoline,1-(ethoxycarbonyl)ethyl-6-nitroindazoline was prepared by alkylation of6-nitroindazoline with ethyl 3-bromopropionate in presence of K₂CO₃. Thedesired product (58%) with high Rfvalue on the TLC in 30% EtOAc: Hexaneswas collected by silica gel column chromatographic purification. ¹H NMR(CDCl₃): δ 8.49 (s, 1H), 8.12 (s, 1H), 8.01 (dd, 1H, J=1.7 and 8.8 Hz),7.82 (d, 1H, J=8.8 Hz), 4.74 (t, 2H, J=6.4 Hz), 4.09 (qt, 2H, J=7.0 Hz),3.03 (t, 2H, J=6.4 Hz), 1.18 (t, 3H, J=7.0 Hz).

Preparation of 6-amino-1-(2-ethoxycarbonylethyl)indazoline

In like manner to the reduction of diethyl2-methyl-2-(3-nitrophenoxy)malonate,1-(2-ethoxycarbonylethyl)-6-nitroindazoline was reduced to provide6-amino-1-(2-ethoxycarbonylethyl)indazoline. ¹H NMR (CDCl₃): δ 7.81 (s,1H), 7.46 (d, 1H, J=8.8 Hz), 6.60 (app s, 1H), 6.55 (dd, 1H, J=2.3 and8.8 Hz), 4.51 (t, 2H, J=7.0 Hz), 4.11 (qt, 2H, J=7.0 Hz), 3.52 (br s,2H), 2.91 (t, 2H, J=7.0 Hz), 1.18 (t, 3H, J=7.0 Hz).

Preparation of 1-(2-ethoxycarbonylethyl)-5-nitroindazoline

In like manner to the preparation of1-(methoxycarbonyl)methyl-5-nitroindazoline,1-(ethoxycarbonyl)ethyl-5-nitroindazoline was prepared by alkylation of5-nitroindazoline with ethyl 3-bromopropionate in presence of K₂CO₃. Thedesired product (43%) with high Rf value on the TLC in 30% EtOAc:Hexanes was collected by silica gel column chromatographic purification.¹H NMR (CDCl₃): δ 8.70 (d, 1H, J=1.7 Hz), 8.27 (dd, 1H, J=2.3 and 8.8Hz), 8.20 (d, 1H, J=1.7 Hz), 7.59 (d, 1H, J=8.8 Hz), 4.70 (t, 2H, J=6.4Hz), 4.07 (qt, 2H, J=7.0 Hz), 3.01 (t, 2H, J=6.4 Hz), 1.16 (t, 3H, J=7.0Hz).

Preparation of 5-amino-1-(2-ethoxycarbonylethyl)indazoline

In like manner to the reduction of diethyl2-methyl-2-(3-nitrophenoxy)malonate,1-(2-ethoxycarbonylethyl)-5-nitroindazoline was reduced to provide5-amino-1-(2-ethoxycarbonylethyl)indazoline. ¹H NMR (CDCl₃): δ 7.78 (s,1H), 7.30 (d, 1H, J=8.8 Hz), 6.91 (d, 1H, J=2.3 Hz), 6.87 (dd, 1H, J=2.3and 8.8 Hz), 4.59 (t, 2H, J=6.4 Hz), 4.08 (qt, 2H, J=7.0 Hz), 3.02 (brs, 2H), 2.92 (t, 2H, J=7.0 Hz), 1.16 (t, 3H, J=7.0 Hz).

Preparation of 5-amino-2-methylindazoline

In like manner to the reduction of diethyl2-methyl-2-(3-nitrophenoxy)malonate, commercially available2-methyl-5-nitroindazoline was reduced to provide5-amino-2-methylindazoline. ¹H NMR (CDCl₃): δ 7.61 (s, 1H), 7.53 (d, 1H,J=8.8 Hz), 6.81 (dd, 1H, J=2.3 and 8.8 Hz), 6.75 (d, 1H, J=2.3 Hz), 4.13(s, 3H), 3.85 (br s, 2H).

7.2.46 Preparation of methyl3-methoxy-4-[(6-nitroindazol-1-yl)methyl]benzoate

In like manner to the preparation of1-(methoxycarbonyl)methyl-6-nitro-indazoline, methyl3-methoxy-4-[(6-nitroindazol-1-yl)methyl]benzoate was prepared byalkylation of 6-nitroindazoline with methyl(4-bromomethyl)-3-methoxybenzoate in presence of K₂CO₃. The desiredproduct (48%) with high R/value on the TLC in 30% EtOAc:hexanes wascollected by silica gel column chromatographic purification. ¹H NMR(CDCl₃): δ 8.50 (d, 1H, J=1.7 Hz), 8.14 (s, 1H), 8.00 (dd, 1H, J=1.8 and8.8 Hz), 7.82 (d, 1H, J=8.8 Hz), 7.56 (s, 1H), 7.54 (d, 1H, J=1.8 Hz),7.07 (d, 1H, J=8.2 Hz), 5.70 (s, 2H), 3.96 (s, 3H), 3.88 (s, 3H). LowR_(f): Methyl 3-methoxy-4-[(6-nitroindazol-2-yl)methyl]benzoate: ¹H NMR(CDCl₃): δ 8.68 (br s, 1H), 8.07 (s, 1H), 7.86 (dd, 1H, J=1.8 and 9.0Hz), 7.72 (d, 1H, J=9.0 Hz), 7.61 (d, 1H, J=7.7 Hz), 7.58 (s, 1H), 7.19(d, 1H, J=7.7 Hz), 5.69 (s, 2H), 3.93 (s, 3H), 3.90 (s, 3H).

Preparation of Methyl 4-[(6-aminoindazol-1-yl)methyl]benzoate

In like manner to the reduction of diethyl2-methyl-2-(3-nitrophenoxy)malonate, methyl3-methoxy-4-[(6-nitroindazol-1-yl)methyl]benzoate was reduced to providemethyl 4-[(6-aminoindazol-1-yl)methyl]benzoate. ¹H NMR (CDCl₃): δ 7.88(s, 1H), 7.53 (d, 1H, J=8.8 Hz), 7.51 (d, 1H, J=8.8 Hz), 7.50 (d, 1H,J=1.7 Hz), 6.67 (d, 1H, J=8.8 Hz), 6.56 (dd, 1H, J=1.7 and 8.8 Hz), 6.45(d, 1H, J=1.2 Hz), 5.50 (s, 2H), 3.94 (s, 3H), 3.87 (s, 3H), 3.79 (br s,2H).

Preparation of Methyl 4-[(6-aminoindazol-2-yl)methyl]benzoate

In like manner to the reduction of diethyl2-methyl-2-(3-nitrophenoxy)malonate, methyl3-methoxy-4-[(6-nitroindazol-2-yl)methyl]benzoate was reduced to providemethyl 4-[(6-aminoindazol-2-yl)methyl]benzoate. ¹H NMR (CDCl₃): δ 7.78(s, 1H), 7.56-7.53 (m, 2H), 7.43 (d, 1H, J=8.8 Hz), 6.98 (d, 1H, J=8.2Hz), 6.81 (app s, 1H), 6.58 (dd, 1H, J=1.8 and 8.8 Hz), 5.53 (s, 2H),3.91 (s, 3H), 3.89 (s, 3H).

7.2.47 Preparation of6-amino-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline

Preparation of 6-nitro-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline

Ester hydrolysis of methyl3-methoxy-4-[(6-nitroindazol-1-yl)methyl]benzoate in presence ofLiOH:H₂O produced the corresponding acid. The acid (1.65 g, 5.04 mmole)thus formed was converted to the acid chloride by reacting with SOCl₂(3.68 mL, 50.45 mmole) at reflux temperature for 5 h. The reactionmixture was cooled to room temperature and concentrated under vacuo. Toacid chloride concentrate dissolved in dry CH₂Cl₂ (75 mL),o-toluylbenzenesulfonamide (0.95 g, 5.54 mmole) and4-(dimethylamino)-pyridine (0.67 g, 5.54 mmole) were added successivelyat room temperature and stirred for 12 h. The reaction mixture wasconcentrated, dissolved in EtOAc (700 mL) and successively treated with2 N HCl (2×100 mL), water (150 mL) and brine (100 mL). Usual workup andpurification by silica gel column chromatography provided the product(1.57 g, 64%). ¹H NMR (DMSO-d₆): δ 8.75 (s, 1H), 8.31 (s, 1H), 8.00 (d,1H, J=8.8 Hz), 7.95-7.91 (m, 2H), 7.50 (d, 1H, J=1.2 Hz), 7.46-7.27 (m,4H), 6.92 (d, 1H, J=7.6 Hz), 5.76 (s, 2H), 3.81 (s, 3H), 2.54 (s, 3H).

Preparation of6-amino-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline

In like manner to the reduction of diethyl2-methyl-2-(3-nitrophenoxy)malonate,6-nitro-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline wasreduced to provide6-amino-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline. ¹HNMR (CDCl₃): δ 7.96 (dd, 1H, J=1.2 and 8.2 Hz), 7.76 (s, 1H), 7.51 (d,1H, J=1.2 Hz), 7.49-7.44 (m, 1H), 7.37 (d, 2H, J=8.8 Hz), 7.34-7.32 (m,1H), 7.30 (d, 1H, J=8.8 Hz), 6.51-6.47 (m, 2H), 6.35 (s, 1H), 5.35 (s,2H), 3.89 (s, 3H), 2.54 (s, 3H).

Preparation of methyl 3-methoxy-4-[(5-nitroindazol-1-yl)methyl]benzoate

In like manner to the preparation of methyl3-methoxy-4-[(6-nitroindazol-1-yl)methyl]benzoate, methyl3-methoxy-4-[(5-nitroindazol-1-yl)methyl]benzoate was prepared byalkylation of 5-nitroindazoline with methyl(4-bromomethyl)-3-methoxybenzoate in presence of K₂CO₃. The desiredproduct (47%) with high Ryvalue on the TLC in 30% EtOAc: Hexanes aseluent was collected by silica gel column chromatographic purification.¹H NMR (CDCl₃): δ 8.73 (d, 1H, J=1.8 Hz), 8.26-8.22 (m, 2H), 7.56 (s,1H), 7.54 (dd, 1H, J=1.8 and 8.2 Hz), 7.49 (d, 1H, J=9.4 Hz), 6.98 (d,1H, J=8.2 Hz), 5.66 (s, 2H), 3.91 (s, 3H), 3.89 (s, 3H). Low R_(f):Methyl 3-methoxy-4-[(5-nitroindazol-2-yl)methyl]benzoate.

Preparation of5-nitro-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline

In like manner to the preparation of6-nitro-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline,5-nitro-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline wasprepared from methyl 3-methoxy-4-[(5-nitroindazol-1-yl)methyl]benzoate.¹H NMR (DMSO-d₆): δ 8.81 (d, 1H, J=2.3 Hz), 8.39 (s, 1H), 8.21 (dd, 1H,J=1.8 and 8.8 Hz), 7.87 (dd, 2H, J=3.6 and 8.8 Hz), 7.48 (d, 1H, J=1.2Hz), 7.39 (dd, 1H, J=1.2 and 8.2 Hz), 7.33-7.15 (m, 3H), 6.85 (d, 1H,J=8.2 Hz), 5.65 (s, 2H), 3.76 (s, 3H), 2.49 (s, 3H).

Preparation of5-amino-1-[2-methoxy-4-(O-toluyl-sulfonamidocarboxy)benzyl]indazoline

In like manner to the preparation of6-amino-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline,5-amino-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline wasprepared by reduction of5-nitro-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline. ¹HNMR (DMSO-d₆): δ 7.87 (dd, 1H, J=1.2 and 7.7 Hz), 7.73 (s, 1H), 7.50 (s,1H), 7.35-7.14 (m, 5H), 6.78 (d, 1H, J=1.8 Hz), 6.75 (s, 1H), 6.53 (d,1H, J=8.2 Hz), 5.44 (s, 2H), 3.82 (s, 3H), 2.50 (s, 3H).

7.2.48 Preparation of 8-amino-4H-imidazo[2,1-c][1,4]-benzoxazine

7.3 Synthesis of 2,4-Pyrimidinediamines

A variety of 2,4-pyrimidinediamines of the invention were synthesizedfrom the above starting materials and intermediates and othercommercially available reagents. Conditions suitable for synthesizingN2,N4-bis-substituted-2,4-pyrimidinediamine compounds (“general SNAr”reaction conditions; Substitution Nucleophilic Aromatic Reaction) areexemplified with N2,N4-bis(4-ethoxyphenyl)-2,4-pyrimdinediamine(R926069) and N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R921218). Conditions suitable for synthesizing asymmetricN2,N4-disubstituted-2,4-pyrimdinediamines are exemplified byN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediame(R926210).

7.3.1 N2,N4-Bis(4-ethoxyphenyl)-2,4-pyrimidinediamine (R926069)

To a solution of 2,4-dichloropyrimidine (0.015 g, 0.1 mmol) in EtOH (1mL) was added 4-ethoxyaniline (0.034 g, 0.025 mmol) and heated in asealed tube at 70-80° C. for 24 h. Upon cooling the reaction was dilutedwith H₂O (10 mL), acidified with 2N HCl, the solid obtained wasfiltered, washed with H₂O and dried to giveN2,N4-bis(4-ethoxyphenyl)-2,4-pyrimidinediamine (R926069). ¹H NMR(CD₃OD): δ 7.63 (d, 1H), 7.45 (d, 2H), J=9 Hz), 7.32 (d, 2H, J=9.3 Hz),6.95 (d, 2H, J=6.9 Hz), 6.87 (d, 2H, J=8.7 Hz), 6.23 (d, 1H, J=7.2 Hz),4.04 (m, 4H), 1.38 (m, 6H); LCMS: ret. time: 25.91 min.; purity: 99.5%;MS (m/e): 351 (MH⁺).

7.3.2 N2,N4-Bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R921218)

A mixture of 2,4-dichloro-5-fluoropyrimidine (0.0167 g, 0.1 mmol) and3-aminophenol (0.033 g, 0.3 mmol) in MeOH: H₂O (1.8:0.2 mL; v/v) wasshaken in a sealed tube at 100° C. for 24 h (or 80° C. for 3 days),cooled to room temperature, diluted with water (15 mL), acidified with2N HCl (pH>2). Upon saturation with sodium chloride it was extractedwith ethyl acetate (3×20 mL), dried over anhydrous sodium sulfate andsolvent was removed. The resulting residue was filtered through a pad ofsilica gel (200-400 mesh) using CH₂Cl₂—>1>10% MeOH in CH₂Cl₂ to obtainthe desired N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R921218). If the reaction scale is large enough, solid of the resultingproduct can be isolated by filtration. ¹H NMR (CDCl₃): δ 7.73 (d, 1H,J=5.1 Hz), 7.12-6.90 (m, 6H), 6.64 (dd, 1H, J=1.8 and 8.1 Hz), 6.53 (dd,1H, J=1.2 and 5.7 Hz); LCMS: ret. time: 16.12 min.; purity: 100%; MS(m/e): 313 (MH⁺).

7.3.3 N2,N4-Bis(4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926017)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-methoxyaniline were reacted toyield N2,N4-bis(4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ 7.67 (d, 1H, J=4.8 Hz), 7.43 (d, 2H, J=9.3 Hz), 7.67 (d, 2H,J=8.7 Hz), 6.87 (d, 2H, J=9.6 Hz), 6.83 (d, 2H, J=8.7 Hz), 3.83 (s, 3H),3.81 (s, 3H); LCMS: ret. time: 22.53 min.; purity: 100%; MS (m/e): 341(MH⁺).

7.3.4N2,N4-Bis(3-fluoro-4-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine(R926018)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-fluoro-4-trifluoromethylanilinewere reacted to yieldN2,N4-bis(3-fluoro-4-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.01 (d, 1H, J=3 Hz), 7.77 (m, 3H), 7.61 (dt, 1H,J=4.2 and 3 Hz), 7.20 (t, 1H, 8.7 Hz), 7.12 (t, 1H, J=9.3 Hz), 6.95 (s,1H), 6.82 (s, 1H); ¹⁹F NMR (CDCl₃): δ −17505 (s, 3F), −17517 (s, 3F),−17525 (s, F), −17537 (s, F), −46835 (s, 1F); LCMS: ret. time: 32.39min.; purity: 95%, MS (m/e): 453 (MH⁺).

7.3.5N2,N4-Bis(3,4-tetrafluoroethylendioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926037)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3,4-tetrafluoroethylenedioxyanilinewere reacted to yieldN2,N4-bis(3,4-tetrafluoroethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.01 (d, 1H, J=3.0 Hz), 7.71 (d, 1H, J=2.4 Hz), 7.70(1H, d, J=2.4 Hz), 7.18 (dd, 2H, J=2.4 and 6 Hz), 7.07 (d, 2H, J=1.8Hz), 7.00 (1H, bs), 6.81 (d, 1H, J=2.7 Hz); ¹⁹F NMR (CDCl₃): −26029(sept, 8F), −46791 (s, C5-F); LCMS: ret. time: 38.20 min.; purity: 85%;MS (m/e): 541 (MH⁺).

7.3.6 N2,N4-Bis(3-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926038)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-trifluoromethoxyaniline werereacted to yieldN2,N4-bis(3-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ 8.03 (bd, 1H), 7.62 (bs, 2H), 7.48 (bd, 1H), 7.39 (t, 1H,J=8.1 Hz), 7.34 (m, 1H), 7.29 (t, 1H, J=7.5 Hz), 7.01 (m, 2H), 6.88 (m,2H); ¹⁹F NMR (CDCl₃): −16447 (s, 3F), −16459 (s, 3F), −46738 (s, 1F);LCMS: ret. time: 33.77 min.; purity: 93%; MS (m/e): 449 (MH⁺).

7.3.7N2,N4-Bis(4-chloro-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine(R926039)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-chloro-3-trifluoromethylanilinewere reacted to yieldN2,N4-bis(4-chloro-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.05 (bs, 1H), 7.89 (bd, 1H), 7.77 (dd, 1H, J=2.4 and9 Hz), 7.65 (dd, 1H, J=2.4 and 8.7 Hz), 7.49 (d, J=8.1 Hz), 7.40 (d, 1H,J=6.2 Hz), 7.03 (s, 1H), 6.91 (s, 1H); ¹⁹F NMR (CDCl₃): δ −17864 (s,3F), −17894 (s, 3F), −46550 (s, 1F); LCMS: ret. time: 38.81 min.;purity: 75%; MS (m/e): 485 (MH⁺).

7.3.8 N2,N4-Bis(3-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R926064)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-ethoxyaniline were reacted toyield N2,N4-bis(3-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ 7.96 (1H, d, J=4.8 Hz), 7.22 (m, 6H), 7.07 (t, 1H, J=1.8 Hz),6.95 (dt, 1H, J=1.2 and 7.2 Hz), 6.77 (m, 2H), 3.88 (q, 4H, J=6.3 Hz),1.33 (two t, 6H, J=6.3 Hz); ¹⁹F NMR (CDCl₃): −46175; LCMS: ret. time:26.86 min.; purity: 97%; MS (m/e): 369 (MH⁺).

7.3.9N2,N4-Bis(3-hydroxy-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926339)

In like manner toN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-hydroxy-4-methoxylaniline werereacted to yieldN2,N4-bis(3-hydroxy-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CD₃OD): δ 7.82 (d, 1H J=4 Hz), 7.18 (m, 2H), 6.95 (m, 2H), 6.83 (m,2H) 3.93 (s, 6H); LCMS: ret. time: 16.63 min.; purity: 97%; MS (m/e):373 (MH⁺).

7.3.10N2,N4-Bis(4-ethoxycarbonylamino-3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926340)

In like manner toN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and4-ethoxycarbonylamino-3-hydroxyaniline were reacted to yieldN2,N4-bis(4-ethoxycarbonylamino-3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.86 (d, 1H J=4 Hz), 7.67 (m, 2H), 7.20 (dd, 1H, J=8Hz, J=4.1 Hz), 7.13 (d, 1H), 6.90 (m, 2H), 4.2 (m, 4H), 1.32 (m, 6H);LCMS: ret. time: 20.92 min.; purity: 98%; MS (m/e): 487 (MH⁺).

7.3.11N2,N4-Bis(-3-hydroxy-4-methylphenyl)-5-fluoro-2,4-pyrimidinediaminediamine(R926341)

In like manner toN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-hydroxy-4-methylaniline werereacted to yieldN2,N4-bis(-3-hydroxy-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CD₃OD): δ 7.83 (d, 1H J=4 Hz), 7.11 (m, 4H), 6.81 (m, 2H), 2.19 (m,6H); LCMS: ret. time: 20.69 min.; purity: 98%; MS (m/e): 341 (MH⁺).

7.3.12N2,N4-Bis[4-(2-methoxyethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926342)

In like manner toN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-(2-methoxyethyloxy)aniline werereacted to yieldN2,N4-bis[4-(2-methoxyethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.89 (d, 1H J=4 Hz), 7.54 (dd, 2H, J=6.8 and 2.7 Hz),7.38 (dd, 2H, J=6.8 and 2.7 Hz), 6.87 (dd, 2H, J=6.8 and 2.7 Hz), 6.82(dd, 2H, J=6.8 and 2.7 Hz) 4.6 (m, 4H), 4.11 (m, 4H), 3.35 (m, 6H);LCMS: ret. time: 21.76 min.; purity: 97%; MS (m/e): 429 (MH⁺).

7.3.13N2,N4-Bis(dihydrobenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediaminediamine(R909237)

In like manner toN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 5-amino-2,3-dihydrobenzofuran werereacted to yieldN2,N4-bis(dihydrobenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediaminediamine.¹H NMR (CD₃OD): δ 7.99 (d, 1H J=4 Hz), 7.22 (m, 4H), 6.81 (m, 2H), 4.55(m, 4H), 3.22 (m, 4H); LCMS: ret. time: 23.80 min.; purity: 98%; MS(m/e): 438 (MH⁺).

7.3.14 N2,N4-Bis(3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926065)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-methoxyaniline were reacted toyield N2,N4-bis(3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ 7.96 (d, 1H, J=5.4 Hz), 7.24 (m, 6H), 7.06 (t, 1H, J=2.4 Hz),7.00 (dt, 1H, J=1.2 Hz), 6.79 (m, 1H), 3.72 (s, 3H), 3.70 (s, 3H); ¹⁹FNMR (CD₃OD): δ −46112; LCMS: ret. time: 23.46 min.; purity: 99%; MS(m/e): 341 (MH⁺).

7.3.15N2,N4-Bis[4-(N,N-dimethylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926086)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-N,N-dimethylaniline were reactedto yieldN2,N4-bis[4-(N,N-dimethylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.84 (d, 1H, J=3.6 Hz), 7.43 (d, 2H, J=8.7 Hz), 7.34(d, 2H, J=8.7 Hz), 7.25 (s, 1H), 6.73 (m, 4H), 6.55 (s, 1H), 2.95 (s,6H), 2.90 (s, 6H); ¹⁹F NMR (CDCl₃): −47770; LCMS: ret. time: 12.48 min.;purity: 99%; MS (m/e): 367 (MH⁺).

7.3.16 N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926109)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3,4-ethylenedioxyaniline werereacted to yieldN2,N4-bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ 7.88 (d, 1H, J=3.6 Hz), 7.23 (d, 1H, J=2.3 Hz), 7.15 (d,1H, J=2.4 Hz), 7.00 (dd, 1H, J=3 and 8.1 Hz), 6.98 (dd, 1H, J=3 and 8Hz), 6.83 (d, 1H, J=8.7 Hz), 6.81 (d, 1H, J=8.7 Hz), 6.7 (s, 1H), 6.58(s, 1H), 4.23 (m, 4H), 4.24 (m, 4H); ¹⁹F NMR (CDCl₃): δ −47445; LCMS:ret. time: 21.81 min.; purity: 96%; MS (m/e): 397 (MH⁺).

7.3.17 N2,N4-Bis(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926110)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3,4-dimethoxyaniline were reacted toyield N2,N4-bis(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ 7.90 (d, 1H, J=1.8 Hz), 7.13 (d, 2H, J=4.8 Hz), 7.08 (d,1H, J=8.7 Hz), 6.94 (d, 2H, J=10.5 Hz), 6.81 (d, 1H, J=8.7 Hz), 6.76 (d,1H, J=8.7 Hz), 6.70 (s, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.74 (s, 3H),3.71 (s, 3H); ¹⁹F NMR (CDCl₃): δ −47433; LCMS: ret. time: 19.64 min.;purity: 95%; MS (m/e): 401 (MH⁺).

7.3.18 N2,N4-Bis[4-(N-morpholino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926114)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-N-morpholinylaniline were reactedto yieldN2,N4-bis[4-N-morpholinyl)phenyl]-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ 7.80 (s, 1H), 7.78 (s, 1H, partially exchanged), 7.76 (bs,1H, partially exchanged), 7.53 (d, 2H, J=8.1 Hz), 7.39 (d, 2H, J=9 Hz),6.93 (d, 2H, J=8.7 Hz), 6.86 (bd, 2H), 3.84 (m, 8H), 3.11 (m, 8H); ¹⁹FNMR (CD₃OD): δ −47697; LCMS: ret. time: 18.15 min.; purity: 99.55%; MS(m/e): 451 (MH⁺).

7.3.19 N2,N4-Bis(4-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine(R926206)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-chloroaniline were reacted toyield N2,N4-bis(4-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CDCl₃+CD₃OD): δ 7.80 (d, 1H, J=4.2 Hz), 7.45 (d, 2H, J=8.7 Hz), 7.33(d, 2H, J=9 Hz), 7.20 (d, 2H, J=8.7 Hz), 7.14 (d, 2H, J=9.6 Hz); LCMS:ret. time: 28.84 min.; purity: 87%; MS (m/e): 349 (MH⁺).

7.3.20 N2,N4-Bis(3-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine(R926209)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-chloroaniline were reacted toyield N2,N4-bis(3-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ 8.08 (d, 1H, J=5.4 Hz), 7.70 (t, 1H, J=1.8 Hz), 7.57 (t, 1H,J=1.2 Hz), 7.54 (m, 1H), 7.35 (m, 4H), 7.28 (t, 1H, J=1.8 Hz), 7.24 (m,1H), 7.22 (t, 1H, J=1.8 Hz); ¹⁹F NMR (CD₃OD): −43631; LCMS: ret. time:28.99 min.; purity: 99%; MS (m/e): 349 (M⁺).

7.3.21 N2,N4-Bis(4-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine(R926222)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-tert-butylaniline were reacted toyield N2,N4-bis(4-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ 7.77 (d, 1H, J=3.9 Hz), 7.47 (d, 2H, J=9 Hz), 7.38 (m,4H), 7.30 (d, 2H, J=8.7 Hz), 1.34 (s, 9H), 1.32 (s, 9H); LCMS: ret.time: 34.09 min.; purity: 93%; MS: 393 (MH⁺).

7.3.22 N2,N4-Bis(3-chloro-4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine(R926223)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-fluoroaniline werereacted to yieldN2,N4-bis(3-chloro-4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃+CD₃OD)): δ 7.81 (d, 1H), 7.60 (m, 1H), 7.58 (m, 1H), 7.38 (m,1H), 7.19 (m, 1H), 7.0 (m, 2H); LCMS: ret. time: 28.98 min.; purity:97%; MS (m/e): 385 (M⁺).

7.3.23 N2,N4-Bis(4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine(R926224)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-fluoroaniline were reacted toyield N2,N4-bis(4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CDCl₃): δ 8.79 (d, 2H, J=5.4 Hz), 7.40 (m, 2H), 7.30 (m, 2H), 6.90 (m,4H); ¹⁹NMR (CDCl₃): −32425 (s, 1F), −32940 (s, 1F), −45525 (s, 1F);LCMS: ret. time: 23.53 min.; purity: 100%; MS (m/e): 317 (MH⁺).

7.3.24 N2,N4-Bis(4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine(R926225)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-methylaniline were reacted toyield N2,N4-bis(4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CDCl₃): δ 7.73 (d, 1H, J=4.2 Hz), 7.43 (d, 2H, J=8.1 Hz), 7.36 (d, 2H,J=8.4 Hz), 7.14 (d, 2H, J=8.4 Hz), 7.10 (d, 2H, J=8.1 Hz), 2.39 (s, 3H),2.35 (s, 3H); LCMS: ret. time: 25.81 min.; purity: 99.65%; MS (m/e): 309(MH⁺).

7.3.25N2,N4-Bis[(4-methoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926240)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and ethyl 4-aminophenoxyacetate werereacted to yieldN2,N4-bis[(4-methoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.8 (bs, 1H), 7.50 (d, 2H, J=9.3 Hz), 7.32 (d, 2H,J=8.41 Hz), 6.88 (m, 4H), 4.72 (s, 2H), 4.70 (s, 2H), 3.79 (s, 3H), 3.78(s, 3H); ¹⁹F NMR (CDCl₃): −47570; LCMS: ret. time: 21.17 min.; purity:95%; MS (m/e): 457 (MH⁺).

7.3.26(+)-N2,N4-Bis[4-methoxycarbonyl(α-methyl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R926254)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and (+)-ethyl2-(4-aminophenoxy)propionate were reacted to yield(+)-N2,N4-bis[4-methoxycarbonyl(α-methyl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.89 (bs, 1H), 7.48 (dd, 2H, J=2.4 and 6.9 Hz), 7.40(dd, 2H, J=1.8 and 6.9 Hz), 6.85 (m, 4H), 6.76 (s, 1H), 6.63 (s, 1H),4.75 (hex, 2H, J=6.3 Hz), 3.77 (s, 3H), 3.76 (s, 3H), 1.62 (t, 6H, J=7.5Hz); LCMS: ret. time: 23.76 min.; purity: 97%; MS (m/e): 485 (MH⁺).

7.3.27N2,N4-Bis[(3-methoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926255)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and ethyl 3-aminophenoxyacetate werereacted to yieldN2,N4-bis[(3-methoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.96 (d, 1H, J=2.4 Hz), 7.71 (t, 1H, J=2.4 Hz), 7.44(m, 2H), 7.21 (m, 3H), 6.96 (dd, 1H, J=1.2 and 7.8 Hz), 6.86 (d, 1H, J=3Hz), 6.53 (m, 1H), 4.64 (s, 2H), 4.60 (s, 2H), 3.79 (s, 6H); LCMS: ret.time: 21.72 min.; purity: 87%; MS (m/e): 457 (MH⁺).

7.3.28 N2,N4-Bis(3-acetyloxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926387)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-acetoxyaniline were reacted toyield N2,N4-bis[(3-acetoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.Alternatively,N2,N4-bis[(3-acetoxyphenyl]-5-fluoro-2,4-pyrimidinediamine can beprepared by acetylation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine with acetylchloride in the presence of pyridine in CH₂Cl₂. ¹H NMR (CDCl₃): δ 8.00(bs, 1H), 7.51-7.25 (m, 8H), 2.32 (s, 3H), 2.28 (s, 3H); LCMS: ret.time: 22.14 min; purity: 100%; MS (m/e): 397 (MH⁺).

7.3.29 N2,N4-Bis(3-benzyloxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926394)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-benzyloxyaniline were reacted toyield N2,N4-bis(3-benzyloxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ 7.98 (bs, 1H), 7.42-6.99 (m, 16H), 6.75 (d, 1H, J=2.4Hz), 6.71 (m, 1H), 6.60 (dd, 1H, J=2.4 and 8.4 Hz), 6.32 (m, 1H), 4.97(s, 2H), 4.94 (s, 2H); LCMS: ret. time: 32.56 min.; purity: 98%; MS(m/e): 493 (MH⁺).

7.3.30 N2,N4-Bis(2-phenylphenyl)-5-fluoro-2,4-pyrimidinediamine(R926398)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-phenylaniline were reacted toyield N2,N4-bis[(2-phenylphenyl]-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CDCl₃): δ 8.35 (m, 1H), 8.0 (s, 1H), 7.85 (s, 1H), 7.45-7.00 (m, 18H);LCMS: ret. time: 30.29 min.; purity: 68%; MS (m/e): 433 (MH⁺).

7.3.31 (R926404) N2,N4-Bis(2-phenylphenyl)-5-methyl-2,4-pyrimidinediamine

In like manner to the preparation of5-fluoro-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-aminobiphenyl and 2,4-dichloro-5-methylpyrimidine were reacted toprovide N2, N4-bis(2-phenylphenyl)-5-methyl-2,4-pyrimidinediamine. LCMS:ret. time: 30.47 min.; purity: 91%; MS (m/e): 429 (MH⁺).

7.3.32N2,N4-Bis[(4-methoxy-3-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926399)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-methoxy-3-phenylaniline werereacted to yieldN2,N4-bis[(4-methoxy-3-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CD₃OD): δ 7.83 (d, 1H, J=4.2 Hz), 7.57 (bd, 1H, J=8.7 Hz), 7.48 (d,1H, J=2.7 Hz), 7.47-7.22 (m, 12H), 6.85 (d, 1H, J=8.7 Hz), 6.78 (d, 1H,9.3 Hz), 3.72 (s, 3H), 3.69 (s, 3H); LCMS: ret. time: 29.97 min.;purity: 92%; MS (m/e): 493 (MH⁺).

7.3.33N2,N4-Bis[(2-methoxy-5-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926400)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-methoxy-5-phenylaniline werereacted to yieldN2,N4-bis[(2-methoxy-5-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CD₃OD): δ 8.03 (d, 1H, J=6.6 Hz), 7.76 (t, 1H, J=2.4 Hz), 7.28-7.10(m, 13H), 7.07 (d, 1H, J=9 Hz), 7.01 (d, 1H, J=8.1 Hz), 3.91 (s, 3H),3.86 (s, 3H); LCMS: ret. time: 18.58 min.; purity: 96%; MS (m/e): MH⁺).

7.3.34N2,N4-Bis[(2-methoxy-5-methyl-4-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926401)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-methoxy-5-methyl-4-phenylanilinewere reacted to yieldN2,N4-bis[(2-methoxy-5-methyl-4-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.00 (d, 1H, J=4.8 Hz), 7.73 (s, 1H), 7.66 (s, 1H),7.43-7.24 (m, 9H), 6.91 (s, 1H), 6.82 (s, 1H), 3.86 (s, 3H), 3.85 (s,3H), 2.14 (s, 3H), 1.99 (s, 3H); LCMS: ret. time: 19.98 min.; purity:99%; MS (m/e): 521 (MH⁺).

7.3.35N2,N4-Bis[(2-methyl-5-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926402)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-methyl-5-phenylaniline werereacted to yieldN2,N4-bis[(2-methyl-5-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CD₃OD): δ 7.84 (bd, 1H), 7.51-7.20 (m, 16H), 2.30 (s, 3H), 2.24 (s,3H); LCMS: ret. time: 18.57 min.; purity: 87%; MS (m/e): 461 (MH⁺).

7.3.36 N2,N4-Bis[(3-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926403)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-phenylaniline were reacted toyield N2,N4-bis[(3-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ 8.02 (d, 1H, J=5.1 Hz), 7.82 (t, 1H, J=1.5 Hz), 7.67 (t, 1H,J=1.8 Hz), 7.58 (dd, 1H, J=1.2 and 7.2 Hz), 7.42-7.24 (m, 15H); LCMS:ret. time: 32.06 min.; purity: 94%; MS (m/e): 433 (MH⁺).

7.3.37 N2,N4-Bis(4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926405)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-acetoxyaniline were reacted toyield N2,N4-bis[(4-hydroxyphenyl]-5-fluoro-2,4-pyrimidinediamine. Afterthe work up it was observed that the acetoxy group was hydrolyzed toafford the N2,N4-bis(4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamineinstead of the corresponding acetate derivative. ¹H NMR (CD₃OD): δ 7.74(d, 1H, J=5.6 Hz), 7.43 (dd, 2H, J=2.1 and 6.6 Hz), 7.28 (dd, 2H, J=2.4and 6.3 Hz), 6.74 (dd, 2H, J=2.4 and 6.3 Hz), 6.66 (dd, 2H, J=2.4 and7.2 Hz); ¹⁹F NMR (CD₃OD): −48116 (d, 1F); LCMS: ret. time: 16.15 min;purity: 100%; MS (m/e): 313 (MH⁺).

7.3.38N2,N4′-Bis(4-hydroxy-3-methylphenyl)-5-fluoro-2,4-pyrimidinediamine(R926469)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-hydroxy-3-methylaniline werereacted to yieldN2,N4-bis[(4-hydroxy-3-methylphenyl]-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CD₃OD): δ 7.64 (d, 1H, J=3.6 Hz), 7.11 (t, 2H, J=9 Hz), 6.70-6.45(m, 4H), 2.15 (s, 3H), 2.09 (s, 3H); ¹⁹F NMR (CD₃OD): −46278; LCMS: ret.time: 15.53; purity: 84%; MS (m/e): 341 (MH⁺).

7.3.39N2,N4-Bis[4-(tert-butoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926574)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and tert-butyl 4-aminophenoxyacetatewere reacted to yieldN2,N4-bis[4-(tert-butoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine¹H NMR (CDCl₃): δ 7.88 (s, 1H), 7.48 (d, 2H, J=8.4 Hz), 7.40 (d, 2H,J=8.7 Hz), 6.86 (m, 4H), 4.52 (s, 2H), 4.48 (s, 2H), 1.49 (s, 9H), 1.48(s, 9H); LCMS: ret. time: 28.48 min.; purity: 95%; MS (m/e): 541 (MH⁺).

7.3.40 N2,N4-Bis(indol-5-yl)-5-fluoro-2,4-pyrimidinediamine (R926582)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 5-aminoindole were reacted to yieldN2,N4-bis(indol-5-yl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time:20.26 min.; purity: 99%; MS (m/e): 359 (MH⁺).

7.3.41N2,N4-Bis(4-cyanomethylphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926319)

In like manner toN2,N4-bis(3-hydroxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine,2,4-dichloro-5-ethoxycarbonylpyrimidine and 4-cyanomethylaniline werereacted to yieldN2,N4-bis(4-cyanomethylphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 8.72 (s, 1H), 7.64 (m, 4H), 7.32 (d, 2H, J=8.7 Hz),7.21 (d, 2H, J=8.4 Hz), 4.3 (q, 2H, J=7.0 Hz), 3.97 (s, 2H), 3.89 (s,2H), 1.32 (3H, J=7 Hz); LCMS: ret. time: 30.83 min.; purity: 90%; MS(m/e): 413 (MH⁺).

7.3.42 N2,N4-Bis(3-indazol-6-yl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926320)

In like manner toN2,N4-bis(3-hydroxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine,2,4-dichloro-5-ethoxycarbonylpyrimidine and 6-aminoindazole were reactedto yield N2,N4-bis(6-indazolyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 8.76 (s, 1H), 7.73 (d, 2H J=8.8), 7.54 (m, 4H), 7.36(d, 2H, J=9.5 Hz), 4.3 (q, 2H, J=7.0 Hz), 1.34 (3H, J=7 Hz); LCMS: ret.time 27.59 min.; purity: 95%; MS (m/e): 415 (MH⁺).

7.3.43 N2,N4-Bis(3-indazol-7-yl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926321)

In like manner toN2,N4-bis(3-hydroxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine,2,4-dichloro-5-ethoxycarbonylpyrimidine and 7-aminoindazole were reactedto yield N2,N4-bis(7-indazolyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 8.70 (s, 1H), 7.54 (d, 2H J=8.4 Hz), 7.37 (m, 6H),4.3 (q, 2H, J=7.0 Hz), 1.33 (3H, J=7 Hz); LCMS: ret. time 23.61 min.;purity: 94%; MS (m/e): 415 (MH⁺).

7.3.44N2,N4-Bis[6-(1,4-benzoxazine-3-onyl)]-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926325)

In like manner toN2,N4-bis(3-hydroxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine,2,4-dichloro-5-ethoxycarbonylpyrimidine and6-amino-1,4-benzoxazine-3-one were reacted to yieldN2,N4-bis[6-(1,4-benzoxazine-3-onyl)]-5-ethoxycarbonyl-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 8.66 (s, 1H), 7.21 (dd, 2H J=8.8 and J=2.2 Hz), 6.89(d, 2H J=8.4 Hz), 4.54 (s, 2H) 4.49 (s, 2H) 4.3 (q, 2H, J=7.0 Hz), 1.33(3H, J=7 Hz); LCMS: ret. time 23.08 min.; purity: 88%; MS (m/e): 477(MH⁺).

7.3.45N2,N4-Bis(4-ethoxycarbonylmethyleneaminophenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926331)

In like manner toN2,N4-bis(3-hydroxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine,2,4-dichloro-5-ethoxycarbonylpyrimidine and4-ethoxycarbonylmethyleneaminoaniline were reacted to yieldN2,N4-bis(4-ethoxycarbonylaminophenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.72 (s, 1H), 7.70 (d, 2H J=8.8 Hz), 7.28 (d, 2H J=8.4Hz), 7.05 (d, 2H, J=8.4 Hz) 6.82 (d, 2H J=8.4 Hz) 4.5 (m, 4H), 4.23 (m,6H) 1.53 (m, 9H); LCMS: ret. time 18.08 min.; purity: 85%; MS (m/e): 537(MH⁺).

7.3.46 N2,N4-Bis(4-ethoxyphenyl)-6-methoxycarbonyl-2,4-pyrimidinediamine(R926058)

In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-6-methoxycarbonylpyrimidine with 4-ethoxyaniline gaveN2,N4-bis(4-ethoxyphenyl)-6-methoxycarbonyl-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ 7.42 (bs, 1H), 7.35 (bd, 4H), 6.85 (bs, 1H), 6.75 (bd,4H), 3.97 (q, 4H, J=4.8 Hz), 3.92 (s, 3H), 1.36 (t, 6H, J=6.3 Hz); LCMS:ret. time: 27.47 min.; purity: 97%; MS (m/e): 409 (MH⁺).

7.3.47 N2,N4-Bis(4-ethoxyphenyl)-5-methyl-2,4-pyrimidinediamine(R926068)

In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-methylpyrimidine with 4-ethoxyaniline gaveN2,N4-bis(4-ethoxyphenyl)-5-methyl-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ 7.55 (s, 1H), 7.40 (d, 2H), 7.21 (d, 2H, J=8.7 Hz), 6.90 (dd,4H, J=8.7 Hz), 4.04 (q, 4H, J=6.6 Hz), 2.17 (m, 6H); LCMS: ret. time:26.51 min.; purity: 95%; MS (m/e): 365 (MH⁺).

7.3.48 N2,N4-Bis(4-ethoxyphenyl)-6-chloro-2,4-pyrimidinediamine(R926072)

In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4,6-trichloropyrimidine with 4-ethoxyaniline gaveN2,N4-bis(4-ethoxyphenyl)-6-chloro-2,4-pyrimidinediamine. ¹H NMR(CDCl₃): δ 7.42 (d, 2H, J=9 Hz), 7.18 (d, 2H, J=8.7 Hz), 6.89 (d, 2H,J=6.3 Hz), 6.84 (d, 2H, J=8.7 Hz), 6.58 (bs, 1H), 4.02 (m, 4H), 1.43 (m,6H); LCMS: ret. time: 83.21 min.; purity: 87%; MS (m/e): 385 (MH⁺).

7.3.49 N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-methyl-2,4-pyrimidinediamine(R926242)

In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-methylpyrimidine with 3,4-ethyleneoxyaniline gaveN2,N4-bis(3,4-ethylenedioxyphenyl)-5-methyl-2,4-pyrimidinediamine. ¹HNMR (CD₃OD): δ 7.75 (bs, 1H), 7.06 (d, 1H, J=2.4 Hz), 6.96 (d, 1H, J=2.1Hz), 6.94 (d, 1H, J=2.1 Hz), 6.85-6.77 (m, 2H), 6.70 (d, 1H, J=9 Hz),4.23 (s, 4H), 4.19 (s, 4H), 2.09 (s, 3H); LCMS: ret. time: 22.01 min.;purity: 100%; MS (m/e): 393 (MH⁺).

7.3.50 N2,N4-Bis(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine(R926243)

In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloropyrimidine with 3,4-ethyleneoxyaniline gaveN2,N4-bis(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine. ¹H NMR(DMSO-d6): δ 10.95 (s, 1H), 10.50 (s, 1H), 7.84 (bd, 2H), 7.24 (bd, 2H),6.79 (bd, 2H), 6.40 (bd, 2H), 4.24 (s, 8H); LCMS: ret. time: 21.68 min.;purity: 100%; MS (m/e): 379 (MH⁺).

7.3.51 N2,N4-Bis(3-hydroxyphenyl)-5-methyl-2,4-pyrimidinediamine(R926248)

In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-methylpyrimidine with 3-hydroxyaniline gaveN2,N4-bis(3-hydroxyphenyl)-5-methyl-2,4-pyrimidinediamine. LCMS: ret.time: 16.76 min.; purity: 100%, MS (m/e): 309 (MH⁺).

7.3.52 N2, N4-Bis(3-hydroxyphenyl)-2,4-pyrimidinediamine (R926249)

In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloropyrimidine with 3-hydroxyaniline gaveN2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: ret. time: 16.21min.; purity: 100%; MS (m/e): 295 (MH⁺).

7.3.53N2,N4-Bis[(4-methoxycarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R926256)

In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloropyrimidine with methyl 4-aminophenoxyacetate gaveN2,N4-bis[(4-methoxycarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.7 (bs, 1H), 10.28 (bs, 1H), 7.84 (d, 1H, J=6.9Hz), 7.48 (bd, 2H), 7.35 (d, 2H, J=8.7 Hz), 6.95 (d, 2H, J=9 Hz), 6.90(d, 2H, J=8.7 Hz), 6.35 (d, 1H, J=6.9 Hz), 4.81 (s, 2H), 4.79 (s, 2H),3.69 (s, 3H), 3.68 (s, 3H); LCMS: ret. time: 21.27 min.; purity: 98%; MS(m/e): 439 (MH⁺).

7.3.54(+)-N2,N4-Bis[4-methoxycarbonyl(alpha-methyl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R926257)

In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloropyrimidine with (+)-methyl 2-(4-aminophenoxy)propionategave(+)-N2,N4-bis[4-methoxycarbonyl(alpha-methyl)methyleneoxyoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 24.09 min.; purity: 90%; MS (m/e): 467 (MH⁺).

7.3.55N2,N4-Bis(4-methoxycarbonylmethyleneoxyphenyl)-5-methyl-2,4-pyrimidinediamine(R926258)

In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-methylpyrimidine with methyl-4-aminophenoxyacetategaveN2,N4-bis(4-methoxycarbonylmethyleneoxyphenyl)-5-methyl-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.21 (s, 1H), 9.65 (s, 1H), 7.78 (s, 1H), 7.42 (dd,2H), J=2.7 and 8.7 Hz), 7.28 (dd, 2H, J=8.1 Hz), 6.94 (d, 2H, J=8.47Hz), 6.85 (d, 2H, J=8.7 Hz), 4.82 (s, 2H), 4.77 (s, 2H), 3.69 (s, 3H),3.68 (s, 3H), 2.12 (s, 3H); LCMS: ret. time: 21.76 min.; purity: 100%;MS (m/e): 453 (MH⁺).

7.3.56(+)-N2,N4-Bis[4-ethoxycarbonyl(alpha-methyl)methyleneoxyphenyl]-5-methyl-2,4-pyrimidinediamine(R926259)

In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-methylpyrimidine with (+)-ethyl2-(4-aminophenoxy)propionate gave(+)-N2,N4-bis[4-ethoxycarbonyl(alpha-methyl)methyleneoxyphenyl]-5-methyl-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.9 (bs, 1H), 9.35 (bs, 1H), 7.79 (s, 1H), 7.43 (dd,2H, J=3.6 and 8.7 Hz), 7.32 (d, 2H, J=7.5 Hz), 6.86 (d, 2H, J=9 Hz),6.78 (d, 2H, J=8.7 Hz), 4.95 (q, 1H, J=7.2 Hz), 4.90 (q, 1H, J=7.2 Hz),4.12 (2q, 4H, J=5.7 Hz), 2.10 (s, 3H), 1.51 (d, 3H, J=6.3 Hz), 1.47 (d,3H, J=6.3 Hz), 1.16 (2t, 6H, J=5.7 Hz); LCMS: ret. time: 27.41 min.;purity: 96%; MS (m/e): 509 (MH⁺).

7.3.57N2,N4-Bis[2-(4-hydroxyphenyl)ethyl]-5-methyl-2,4-pyrimidinediamine(R926397)

In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-methylpyrimidine with 2-(4-hydroxyphenyl)ethylaminegave N2,N4-bis[2-(4-hydroxyphenyl)ethyl]-5-methyl-2,4-pyrimidinediamine.LCMS: ret. time: 19.94 min.; purity: 100%; MS (m/e): 365 (MH⁺).

7.3.58 N2,N4-Bis-(3,4-dimethoxpenyl)-5-nitro-2,4-pyrimidinediamine(R940089)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-nitropyrimidine with 3,4-dimethoxyaniline gaveN2,N4-bis-(3,4-dimethoxyphenyl)-5-nitro-2,4-pyrimidinediamine. LCMS:ret. time: 28.30 min.; purity: 100%; MS (m/e): 428 (MH⁺); ¹H NMR(CDCl₃): δ 10.30 (1H, s), 9.14 (1H, s), 7.52 (1H, s), 7.08 (3H, m), 7.00(1H, d, J=8.4 Hz), 6.84 (1H, d, J=8.4 Hz), 6.76 (1H, d, J=8.4 Hz), 3.90(3H, s), 3.87 (3H, s), 3.68 (3H, s), 3.60 (3H, s).

7.3.59 N2,N4-Bis-(4-ethoxypenyl)-5-nitro-2,4-pyrimidinediamine (R940090)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-nitropyrimidine with 4-ethoxyaniline gaveN2,N4-bis-(4-ethoxyphenyl)-5-nitro-2,4-pyrimidinediamine. LCMS: ret.time: 35.91 min.; purity: 100%; MS (m/e): 396 (MH⁺); ¹H NMR (CDCl₃): δ10.25 (1H, s), 9.11 (1H, s), 7.44 (2H, d, J=8.6 Hz), 7.37 (2H, d, J=9Hz), 6.88 (2H, d, J=8.6 Hz), 6.80 (2H, d, J=8.6 Hz), 4.06 (2H, q, J=7.2Hz), 4.02 (2H, q, J=7.2 Hz), 1.45 (3H, t, J=7.2 Hz), 1.42 (3H, t, J=7.2Hz).

7.3.60 N2,N4-Bis-(3,4-ethylenedioxyphenyl)-5-nitro-2,4-pyrimidinediamine(R940095)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-nitropyrimidine with 3,4-ethylenedioxyaniline gaveN2,N4-bis-(3,4-ethylenedioxyphenyl)-5-nitro-2,4-pyrimidinediamine. LCMS:ret. time: 30.78 min.; purity: 100%; MS (m/e): 424 (MH⁺); ¹H NMR(CDCl₃): δ 10.21 (1H, s), 9.10 (1H, s), 7.40 (1H, s), 7.11-6.71 (6H, m),4.29 (4H, s), 4.25 (4H, s).

7.3.61N2,N4-Bis-[(4-ethoxycarbonylmethyleneoxy)phenyl]-5-nitro-2,4-pyrimidinediamine(R940096)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-nitropyrimidine with ethyl-4-aminophenoxyacetate gaveN2,N4-bis-[(4-ethoxycarbonylmethyleneoxy)phenyl]-5-nitro-2,4-pyrimidinediamine.LCMS: ret. time: 32.48 min.; purity: 94%; MS (m/e): 512 (MH⁺); ¹H NMR(CDCl₃): δ 10.22 (1H, s), 9.13 (1H, s), 7.50 (1H, s), 7.45 (2H, d, J=8.7Hz), 7.38 (2H, d, J=8.7 Hz), 6.93 (2H, d, J=8.7 Hz), 6.83 (2H, d, J=8.7Hz), 4.67 (2H, s), 4.63 (2H, s), 4.29 (2H, q, J=7.2 Hz, 4.28 (2H, q,J=7.2 Hz), 1.31 (3H, t, J=7.2 Hz), 1.30 (3H, t, J=7.2 Hz).

7.3.62N2,N4-Bis-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-nitro-2,4-pyrimidinediamine(R940100)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-nitropyrimidine with2,2-difluoro-5-amino-1,3-benzodioxole gaveN2,N4-bis-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-nitro-2,4-pyrimidinediamine.LCMS: ret. time: 38.15 min.; purity: 96%; MS (m/e): 467 (M⁺); ¹H NMR(CDCl₃): δ 10.76 (1H, s), 10.49 (1H, s), 9.20 (1H, s), 7.74 (2H, s),7.56 (1H, d, J=11.4 Hz), 7.33 (2H, m), 7.20 (1H, m).

7.3.63N2,N4-Bis-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R940215)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-fluoropyrimidine with 3,5-dichloro-4-hydroxyanilinegaveN2,N4-bis-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 21.26 min.; purity: 88%; MS (m/e): 450 (M⁺); ¹H NMR(DMSO-d6): δ 9.96 (1H, s), 9.59 (1H, s), 9.47 (1H, s), 9.37 (1H, s),8.22 (1H, d, J=3.6 Hz), 7.79 (2H, s), 7.74 (2H, s).

7.3.64N2,N4-Bis-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine(R940216)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-fluoropyrimidine with3-chloro-4-hydroxy-5-methylaniline gaveN2,N4-bis-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 20.55 min.; purity: 99%; MS (m/e): 410 (MH⁺); ¹H NMR(DMSO-d6): δ 9.23 (1H, s), 9.07 (1H, s), 8.99 (1H, s), 8.66 (1H, s),8.13 (1H, d, J=3.6 Hz), 7.59 (2H, t, J=3.1 Hz), 7.50 (1H, d, J=2.3 Hz),7.34 (1H, d, J=2.3 Hz), 2.27 (3H, s), 2.18 (3H, s).

7.3.65N2,N4-Bis-(2,3-dimethyl-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R940217)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-fluoropyrimidine with 2,3-dimethyl-4-hydroxyanilinegaveN2,N4-bis-(2,3-dimethyl-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 19.07 min.; purity: 99%; MS (m/e): 369 (MH⁺); ¹H NMR(DMSO-d6): δ 9.21 (1H, s), 8.99 (1H, s), 8.63 (1H, s), 7.92 (1H, s),7.84 (1H, d, J=3.6 Hz), 6.94 (1H, d, J=8.5 Hz), 6.85 (1H, d, J=8.5 Hz),6.70 (1H, d, J=8.5 Hz), 6.58 (1H, d, J=8.5 Hz), 2.12 (3H, s), 2.06 (3H,s), 2.02 (3H, s), 1.94 (3H, s).

7.3.66 N2,N4-Bis-(4-Acetamidophenyl)-5-fluoro-2,4-pyrimidinediamine(R940222)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-fluoropyrimidine with 4-acetamidoaniline gaveN2,N4-bis-(4-acetamidophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret.time: 14.82 min.; purity: 95%; MS (m/e): 395 (MH⁺); ¹H NMR (DMSO-d6): δ10.33 (1H, s), 10.14 (1H, s), 10.07 (2H, s), 8.39 (1H, d, J=5.1 Hz),7.64 (8H, m), 2.15 (3H, s), 2.13 (3H, s).

7.3.67 N2,N4-Bis(3-isopropylphenyl)-5-fluoro-2,4-pyrimidinediamineR940297

In like manner to the preparation ofN2,N4-bis-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-isopropylaniline were reacted togive N2,N4-bis-(3-isopropylphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 29.58 min.; Purity: 98%; MS (m/e): 365 (MH⁺); ¹H NMR(DMSO-d6): δ 10.5 (1H, s), 10.34 (1H, s), 8.41 (1H, d, J=5.1 Hz), 7.62(1H, d, J=8.1 Hz), 7.53 (1H, s), 7.43 (1H, d, J=8.1 Hz), 7.37 (2H, m),7.29 (1H, t, J=8.1 Hz), 7.19 (1H, d, J=7.8 Hz), 7.08 (1H, d, J=7.8 Hz),2.88 (2H, m), 1.25 (6H, d, J=7.2 Hz), 1.201 (6H, d, J=7.2 Hz).

7.3.68 N2,N4-Bis(3,4,5-trimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926688)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3,4,5-trimethoxyaniline were reactedto yieldN2,N4-bis(3,4,5-trimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 19.55 min.; purity: 99%; MS (m/e): 461 (MH⁺).

7.3.69 N2,N4-Bis(2-methyl-5-phenylphenyl)-5-bromo-2,4-pyrimidinediamineR925800

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-bromo-2,4-dichloropyrimidine and 5-phenyl-ortho-toluidine were reactedto yieldN2,N4-bis(2-methyl-5-phenylphenyl)-5-bromo-2,4-pyrimidinediamine. LCMS:ret. time: 19.54 min.; purity: 90%; MS (m/e): 422 (MH⁺).

7.3.70N2,N4-Bis(2-methoxy-5-methyl-4-phenylphenyl)-5-bromo-2,4-pyrimidinediamine(R925801)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-bromo-2,4-dichloropyrimidine 5-methyl-4-phenyl-ortho-anisidine werereacted to yieldN2,N4-bis(2-methoxy-5-methyl-4-phenylphenyl)-5-bromo-2,4-pyrimidinediamine.LCMS: ret. time: 20.99 min.; purity: 85%; MS (m/e): 583 (MH⁺).

7.3.71 N2,N4-Bis(indol-6-yl)-5-fluoro-2,4-pyrimidinediamine (R926594)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 6-aminoindole were reacted to yieldN2,N4-bis(indol-6-yl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time:22.39 min.; purity: 85%; MS (m/e): 359 (MH⁺).

7.3.72 N2,N4-Bis(2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine (R926604)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-methoxycarbonyl-5-aminobenzofuranwere reacted to yield N2,N4-bis(2-methoxycarbonylbenzofuran-5-yl))-5-fluoro-2,4-pyrimidinediamine. ¹H NMR (DMSO-d6): δ10.3 (bs, 1H), 10.05 (bs, 1H), 8.25 (d, 1H, J=5.4 Hz), 8.06 (s, 1H),7.94 (s, 1H), 7.77-7.49 (m, 5H), 7.36 (bs, 1H), 3.89 (s, 3H), 3.87 (s,3H).

7.3.73N2,N4-Bis[4-(methoxycarbonylmethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926605)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and ethyl 4-aminophenyl acetate werereacted to yieldN2,N4-bis[4-(methoxycarbonylmethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine.The cross esterification reaction of ethyl ester to obtain thecorresponding methyl ester was observed. ¹H NMR (CDCl₃): δ 10.62 (s,1H), 8.06 (s, 1H), 7.69 (d, 1H, J=4.5 Hz), 7.53 (d, 2H, J=8.1 Hz), 7.43(d, 2H, J=8.7 Hz), 7.30 (d, 2H, J=8.4 Hz), 7.20 (d, 2H, J=8.4 Hz), 3.73(s, 3H), 3.72 (s, 3H), 3.67 (s, 2H), 3.63 (s, 2H).

7.3.74N2,N4-Bis(2-ethoxycarbonylindol-5-yl)-5-fluoro-2,4-pyrimidinediamine(R926616)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-ethoxycarbonyl-5-indoleamine werereacted to yieldN2,N4-bis(2-ethoxycarbonylindol-5-yl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (DMSO-d6): δ 11.83 (s, 1H), 11.63 (s, 1H), 9.21 (s, 1H), 8.99 (s,1H), 8.08 (s, 1H), 8.01 (m, 2H), 7.49-7.22 (m, 4H), 6.92 (s, 1H), 6.63(s, 1H), 4.29 (q, 4H, J=7.2 Hz), 1.32 (m, 6H); LCMS: ret. time: 24.74min.; purity: 99%; MS (m/e): 503 (MH⁺).

7.3.75 N2,N4-Bis(coumarin-6-yl)-5-fluoro-2,4-pyrimidinediamine (R926617)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 6-aminocoumarin were reacted toyield N2,N4-bis(coumarin-6-yl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(DMSO-d6): δ 8.17 (d, 2H, J=3.6 Hz), 7.97-7.74 (m, 5H), 7.40 (1H, d,J=8.7 Hz), 7.30 (d, 1H, J=9 Hz), 6.50 (d, 1H, J=10.2 Hz), 6.40 (d, 1H,J=9.3 Hz); LCMS: ret. time: 19.05 min.; purity: 94%; MS (m/e): 417(MH⁺).

7.3.76N2,N4-Bis(4-methoxymethyl)coumarin-7-yl)-5-fluoro-2,4-pyrimidinediamine(R926620)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 7-amino-4-methoxymethylcoumarin werereacted to yieldN2,N4-bis(coumarin-7-yl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(DMSO-d6): δ 10.38 (s, 1H), 8.42 (d, 1H, J=3 Hz), 8.28 (m, 1H),8.05-7.93 (m, 2H), 7.77-7.50 (m, 4H), 6.31 (s, 1H), 6.29 (s, 1H), 4.66(s, 2H), 4.65 (s, 2H), 3.43 (s, 3H), 3.41 (s, 3H); LCMS: MS (m/e): 505(MH⁺).

7.3.77 N2,N4-Bis(3-(hydroxymethyl)phenyl)-5-fluoro-2,4-pyrimidinediamine(R925757)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-aminobenzylalcohol were reacted toyield N2,N4-bis(3-(hydroxymethyl)phenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.90 (d, 1H, J=3.3 Hz), 7.71 (m, 1H), 7.61 (d, 1H,J=6.9 Hz), 7.50 (d, 1H, J=6.0), 7.47 (s, 1H), 7.31 (t, 1H, J=8.1 Hz),7.22 (t, 1H, J=8.1 Hz), 7.10 (d, 1H, J=6.9), 6.97 (d, 1H, J=7.5 Hz),4.63 (s, 4H); LCMS: ret. time: 15.36 min.; purity: 100%; MS (m/e): 342(MH⁺).

7.3.78N2,N4-Bis[(2R)-hydroxy-(1S)-methyl-2-phenylethyl]-5-fluoro-2,4-pyrimidinediamine(R925767)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and (1R,2S)-(−)-norephedrine werereacted to yield N2,N4-bis[(2R)-hydroxy-(1S)-methyl-2-phenylethyl]-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(acetone-d6): δ 7.67 (s, 1H), 7.49-7.42 (m, 4H), 7.38-7.19 (m, 6H), 6.09(d, 1H, J=9.0 Hz), 5.73 (d, 1H, J=7.5 Hz), 5.61 (d, 1H, J=9.3 Hz), 5.04(d, 1H, J=3.6 Hz), 4.97 (d, 1H, J=2.7 Hz), 4.74 (bs, 1H), 4.48 (bs, 1H),4.30-4.25 (m, 1H), 1.09 (d, 1H, J=6.9 Hz), 1.03 (d, 1H, J=6.6 Hz); LCMS:ret. time: 21.56 min.; purity: 98%; MS (m/e): 397 (MH⁺).

7.3.79 N2,N4-Bis(2-hydroxy-2-phenylethyl)-5-fluoro-2,4-pyrimidinediamine(R925768)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-amino-1-phenylethanol were reactedto yieldN2,N4-bis(2-hydroxy-2-phenylethyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (acetone-d6): δ 8.15 (s, 1H), 7.46-7.22 (m, 10H), 5.01 (dd, 1H),4.91 (dd, 1H), 4.78 (dd, 1H), 3.86-3.18 (m, 5H); LCMS: ret. time: 19.64min.; purity: 89%; MS (m/e): 369 (MH⁺).

7.3.80 N2,N4-Bis(furfuryl)-5-fluoro-2,4-pyrimidinediamine (R925769)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and furfurylamine were reacted to yieldN2,N4-bis(furfuryl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR (CDCl₃): δ7.72 (bs, 1H), 7.38 (dd, 2H, J=1.8 and 7.5 Hz), 6.34-6.30 (m, 2H), 6.22(dd, 2H, J=2.4 and 9.9 Hz), 5.163 (bs, 2H), 4.63 (d, 2H, J=6.0), 4.54(d, 2H, J=6.0).; ¹⁹F NMR (CDCl₃): −48621; LCMS: ret. time: 97.27 min.;purity: 97%; MS (m/e): 289 (MH⁺).

7.3.81 N2,N4-Bis(piperonyl)-5-fluoro-2,4-pyrimidineamine (R925770)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and piperonylamine were reacted to yieldN2,N4-bis(piperonyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR (CDCl₃): δ7.60 (bs, 1H), 6.78-6.69 (m, 6H), 5.93 (s, 2H), 5.91 (s, 2H), 4.51 (d,2H, J=5.7 Hz), 4.43 (d, 2H, J=5.1 Hz); ¹⁹F NMR (CDCl₃): −45257; LCMS:ret. time: 22.06 min.; purity: 96%; MS (m/e): 397 (MH⁺).

7.3.82 N2,N4-Dibenzyl-5-fluoro-2,4-pyrimidinediamine (R925772)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and benzylamine were reacted to yieldN2,N4-bis(benzyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR (CDCl₃): δ 7.69(bs, 1H), 7.35-7.24 (m, 10H), 5.63 (bs, 1H), 5.27 (bs, 1H), 4.61 (d, 2H,J=6.0 Hz), 4.55 (d, 2H, J=6.0 Hz); ¹⁹F NMR (CDCl₃): −48580; LCMS: ret.time: 23.73 min.; purity: 100%; MS (m/e): 309 (MH⁺).

7.3.83N2,N4-Bis(3,4-methylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R925776)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3,4-methylenedioxyaniline werereacted to yieldN2,N4-bis(3,4-methylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ 7.86 (bs, 1H), 7.27 (m, 1H), 7.19 (m, 1H), 6.89 (dd, 2H,J=2.1 and 8.1 Hz), 6.80 (dd, 2H, J=1.8 and 8.1 Hz), 6.73 (t, 2H, J=8.1Hz), 5.97 (s, 2H), 5.92 (s, 2H); ¹⁹F NMR (CDCl₃): −47591; LCMS: ret.time: 21.74 min.; purity: 97%; MS (m/e): 369 (MH⁺).

7.3.84N2,N4-Bis[2-(4-hydroxyphenyl)ethyl]-5-fluoro-2,4-pyrimidinediamine(R925791)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and tyramine were reacted to yieldN2,N4-bis[2-(4-hydroxyphenyl)ethyl]-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (DMSO-d6): δ 9.17 (bs, 1H), 8.22 (bs, 1H), 6.99 (d, 4H, J=8.1 Hz),6.65 (d, 4H, J=8.1 Hz), 3.48-3.43 (m, 4H), 2.72 (t, 4H, J=7.7 Hz); LCMS:ret. time: 19.19 min.; purity: 100%; MS (m/e): 369 (MH⁺).

7.3.85 N2,N4-Bis(4-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine (R945057)

In like manner to the preparation ofN2,N-4-bis(3-hydroxyphenyl)-5-fluoro-4-pyrimidineamine,4-aminobenzonitrile and 2,4-dichloro-5-fluoropyrimidine gaveN2,N4-bis(4-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(DMSO-d6): δ 7.26 (d, J=8.7 Hz, 2H), 7.36 (d, J=9.0 Hz, 2H), 7.43 (d,J=8.7 Hz, 2H), 7.60 (d, J=8.7 Hz, 2H), 7.86 (d, J=3.6 Hz, 1H), 9.49 (br,1H, NH), 9.51 (br, 1H, NH); ¹⁹F NMR (282 MHz, DMSO-d6): δ −161.48; LC:27.15 min.; 100%; MS (m/e): 331.00 (MH⁺).

7.3.86 N2,N4-Bis(4-ethylphenyl)-5-fluoro-2,4-pyrimidinediamine (R926234)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-ethylaniline were reacted to yieldN2,N4-bis(4-ethylphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR (CDCl₃):δ 8.83 (bs, 1H), 7.77 (d, 1H. J=3.9 Hz), 7.48 (d, 2H, J=8.7 Hz), 7.40(d, 2H, J=8.7 Hz), 7.31 (bs, 1H), 7.18 (d, 2H, J=8.7 Hz), 7.11 (d, 2H,J=8.7 Hz), 2.68-2.61 (m, 4H), 1.28-1.21 (m, 6H); LCMS: ret. time: 29.17min.; purity: 100%; MS (m/e): 337 (MH⁺).

7.3.87N2,N4-Bis(3-chloro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926675)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-hydroxyaniline werereacted to yieldN2,N4-bis(3-chloro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CD₃OD): δ 7.83 (d, 1H, J=4.2 Hz), 7.59 (d, 1H, J=2.4 Hz), 7.53 (d,1H, J=2.4 Hz), 7.40 (dd, 1H, J=2.4 and 8.7 Hz), 7.20 (dd, 1H, J=2.4 and8.7 Hz), 6.89 (d, 1H, J=8.7 Hz), 6.81 (d, 1H, J=8.7 Hz); ¹⁹F NMR(CD₃OD): −47862; LCMS: ret. time: 17.89 min.; purity: 99%; MS (m/e): 382(MH⁺).

7.3.88N2,N4-Bis[3-chloro-4-(ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926676)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and3-chloro-4-(ethoxycarbonylmethyleneoxy)aniline were reacted to yieldN2,N4-bis[3-chloro-4-(ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.93 (bs, 1H), 7.67-7.65 (m, 2H), 7.41 (dd, 1H, J=3.0and 9.3 Hz), 7.26 (dd, 1H, J=2.7 and 9.3 Hz), 6.92-6.85 (m, 3H), 6.69(d, 1H, J=2.4 Hz), 4.71 (s, 2H), 4.66 (s, 2H), 4.32-4.23 (m, 4H),1.33-1.27 (m, 6H); ¹⁹F NMR (CDCl₃): −47274; LCMS: ret. time: 27.51 min.;purity: 97%; MS (m/e): 553 (M⁺).

7.3.89N2,N4-Bis(3-fluoro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926681)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-fluoro-4-hydroxyaniline werereacted to yieldN2,N4-bis(3-fluoro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ 7.83 (d, 1H), 7.53 (dd, 1H), 7.42 (dd, 1H), 7.22 (dq,1H), 7.03 (dq, 1H), 6.89 (d, 1H), 6.83 (s, 1H), 6.80 (s, 1H), 6.78 (d,1H); ¹⁹F NMR (CDCl₃): −390060,−39165,−47835; LCMS: ret. time: 15.27min.; purity: 95%; MS (m/e): 349 (MH⁺).

7.3.90 N2,N4-Bis(3-acetamidophenyl)-5-fluoro-2,4-pyrimidinediamine(R926682)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-aminoacetanilide were reacted toyield N2,N4-bis(3-acetamidophenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (DMSO-d6): δ 10.24 (bs, 1H), 10.03 (s, 1H), 9.94 (s, 1H), 8.20 (d,1H, J=4.8 Hz), 7.91 (bs, 1H), 7.68 (bs, 1H), 7.43 (d, 1H, J=8.1 Hz),7.35-7.30 (m, 2H), 7.24-7.19 (m, 2H), 7.11 (t, 1H, J=8.1 Hz), 2.03 (s,3H), 2.01 (s, 3H); LCMS: ret. time: 15.10 min.; purity: 99%; MS (m/e):395 (MH⁺).

7.3.91N2,N4-Bis(2-fluoro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926683)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-fluoro-4-hydroxyaniline werereacted to yieldN2,N4-bis(2-fluoro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (DMSO-d6): δ 9.78 (s, 1H), 9.50 (s, 1H), 8.75 (s, 1H), 8.06 (s, 1H),7.87 (d, 1H, J=4.2 Hz), 7.25-7.18 (m, 2H), 6.61 (dd, 1H, J=2.4 and 12.3Hz), 6.56-6.47 (m, 2H), 6.39 (dd, 1H, J=1.8 and 8.7 Hz); LCMS: ret.time: 15.52 min.; purity: 99%; MS (m/e): 349 (MH⁺).

7.3.92 N2,N4-Bis(4-isopropoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926701)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-isopropoxyaniline were reacted toyield N2,N4-bis(4-isopropoxy)phenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ 7.89 (bs, 1H), 7.47 (d, 2H, J=8.7 Hz), 7.38 (d, 2H, J=9.0Hz), 6.87 (d, 2H, J=9.0 Hz), 6.83 (d, 2H, J=8.7 Hz); LCMS: ret. time:27.51 min.; purity: 98%; MS (m/e): 397 (MH⁺).

7.3.93 N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine(R925771)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-bromo-2,4-dichloropyrimidine and 3,4-ethylenedioxyaniline were reactedto yieldN2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine. ¹H NMR(CDCl₃): δ 8.07 (bs, 1H), 7.16 (d, 1H, J=3.0 Hz), 7.10 (d, 1H, J=2.7Hz), 6.98-6.93 (m, 2H), 6.90-6.75 (m, 3H), 4.28-4.21 (m, 8H); LCMS: ret.time: 22.61 min.; purity: 100%; MS (m/e): 458 (MH⁺).

7.3.94 N2,N4-Bis(3-hydroxyphenyl)-5-bromo-2,4-pyrimidinediamine(R925778)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-bromo-2,4-dichloropyrimidine and 3-aminophenol were reacted to yieldN2,N4-bis(3-hydroxyphenyl)-5-bromo-2,4-pyrimidinediamine. ¹H NMR(DMSO-d6): δ 9.99 (bs, 1H), 9.34 (bs, 1H), 8.30 (s, 1H), 7.15 (t, 1H,J=8.4 Hz), 7.06-6.97 (m, 2H), 6.94-6.92 (m, 2H), 6.80 (bs, 1H), 6.62 (s,1H, J=8.1 Hz), 6.43 (d, 1H, J=7.8 Hz); LCMS: ret. time: 18.48 min.;purity: 97%; MS (m/e): 374 (MH⁺).

7.3.95N2,N4-Bis[4-(ethoxycarbonylmethyleneoxy)phenyl]-5-bromo-2,4-pyrimidinediamine(R925779)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-bromo-2,4-dichloropyrimidine and ethyl 4-aminophenoxyacetate werereacted to yieldN2,N4-bis[4-(ethoxycarbonylmethyleneoxy)phenyl]-5-bromo-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.12 (s, 1H), 8.48 (s, 1H), 8.11 (s, 1H), 7.42 (d,4H, J=8.7 Hz), 6.89 (d, 2H, J=9.0 Hz), 6.71 (d, 2H, J=9.3 Hz), 4.78 (s,2H), 4.66 (s, 2H), 4.20-4.10 (m, 4H), 1.23-1.16 (m, 6H); LCMS: ret.time: 25.82 min.; purity: 94%; MS (m/e): 546 (MH⁺).

7.3.96 N2,N4-Bis[2-(4-hydroxyphenyl)ethyl]-5-bromo-2,4-pyrimidinediamine(R925792)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-bromo-2,4-dichloropyrimidine and tyramine were reacted to yieldN2,N4-bis[2-(4-hydroxyphenyl)ethyl]-5-bromo-2,4-pyrimidinediamine. ¹HNMR (DMSO-d6): δ 7.83 (s, 1H), 6.96 (d, 4H, J=8.1 Hz), 6.63 (d, 4H,J=8.1 Hz), 3.54-3.42 (m, 2H), 2.74-2.66 (m, 2H), 2.74-2.66 (m, 4H); ret.time: 20.10 min.; purity: 100%; MS (m/e): 430 (MH⁺).

7.3.97 N2,N4-Bis(2-phenylphenyl)-5-bromo-2,4-pyrimidinediamine (R925798)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-bromo-2,4-dichloropyrimidine and 2-aminobiphenyl were reacted to yieldN2,N4-bis(2-phenylphenyl)-5-bromo-2,4-pyrimidinediamine. ¹H NMR (CDCl₃):δ 8.34 (d, 1H, J=8.1 Hz), 8.27 (d, 1H, J=8.1 Hz), 8.00 (s, 1H),7.51-7.18 (m, 17H), 6.95 (s, 1H); LCMS: ret. time: 18.87 min.; purity:97%; MS (m/e): 495 (MH⁺).

7.3.98 N2,N4-Bis(2-methoxy-5-phenylphenyl)-5-bromo-2,4-pyrimidinediamine(R925799)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-bromo-2,4-dichloropyrimidine and 5-phenyl-ortho-anisidine were reactedto yieldN2,N4-bis(2-methoxy-5-phenylphenyl)-5-bromo-2,4-pyrimidinediamine. ¹HNMR (DMSO-d6): δ 8.26 (m, 2H), 8.05 (m, 2H), 7.39-7.21 (m, 12H), 7.17(dd, 1H, J=2.4 and 8.1 Hz), 7.11 (d, 1H, J=8.7 Hz), 7.05 (d, 1H, J=9.0Hz), 3.88 (s, 3H), 3.83 (s, 3H); LCMS: ret. time: 20.51 min.; purity:98%; MS (m/e): 554 (MH⁺).

7.3.99 N2,N4-Bis(4-methoxy-3-phenylphenyl)-5-bromo-2,4-pyrimidinediamine(R925802)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, with theaddition of triethylamine, 5-bromo-2,4-dichloropyrimidine and3-phenyl-para-anisidine hydrochloride were reacted to yieldN2,N4-bis(4-methoxy-3-phenylphenyl)-5-bromo-2,4-pyrimidinediamine. ¹HNMR (DMSO-d6): δ 8.26 (m, 2H), 8.06 (m, 2H), 7.38-7.25 (m, 12H), 7.18(dd, 1H, J=2.4 and 8.1 Hz), 7.12 (d, 1H, J=8.7 Hz), 7.05 (d, 1H, 8.7Hz), 3.89 (s, 3H), 3.83 (s, 3H); LCMS: ret. time: 36.77 min.; purity:98%; MS (m/e): 554 (MH⁺).

7.3.100 N2,N4-Bis(3-phenylphenyl)-5-bromo-2,4-pyrimidinediamine(R925803)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-bromo-2,4-dichloropyrimidine and 3-aminobiphenyl were reacted to yieldN2,N4-bis(3-phenylphenyl)-5-bromo-2,4-pyrimidinediamine. ¹H NMR(DMSO-d6): δ 9.86 (bs, 1H), 9.20 (bs 1H), 8.33 (s, 1H), 7.79 (bs, 1H),7.18 (bs, 1H), 7.61 (d, 1H), 7.56-7.51 (m, 2H), 7.48-7.23 (m, 11H),7.17-7.04 (m, 2H); LCMS: ret. time: 19.52 min.; purity: 80%; MS (m/e):494 (MH⁺).

7.3.101 N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-cyano-2,4-pyrimidinediamine(R925773)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-cyanopyrimidine and 3,4-ethylenedioxyaniline were reactedto yieldN2,N4-bis(3,4-ethylenedioxyphenyl)-5-cyano-2,4-pyrimidinediamine. ¹H NMR(DMSO-d6): δ 9.69 (bs, 1H), 9.28 (bs, 1H), 8.40 (s, 1H), 7.16-6.89 (m,4H), 6.79 (d, 1H, J=9.0 Hz), 6.65 (bs, 1H), 4.22 (s, 4H), 4.16 (s, 4H);LCMS: ret. time: 24.42 min.; purity: 93%; MS (m/e): 404 (MH⁺).

7.3.102 N2,N4-Bis(3-hydroxyphenyl)-5-cyano-2,4-pyrimidinediamine(R925774)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-cyanopyrimidine and 3-hydroxyaniline were reacted toyield N2,N4-bis(3-hydroxyphenyl-5-cyano-2,4-pyrimidinediamine. ¹H NMR(DMSO-d6): δ 9.73 (bs, 1H), 9.40 (s, 1H), 9.33 (bs, 1H), 9.24 (s, 1H),8.47 (s, 1H), 7.20 (d, 1H, J=7.5 Hz), 7.11 (t, 1H, J=7.5 Hz), 7.09-7.02(m, 2H), 6.99-6.89 (m, 3H), 6.54 (d, 1H, J=7.2 Hz), 6.37 (dd, 1H, J=1.8and 8.4 Hz); LCMS: ret. time: 19.71 min.; purity: 97%; MS (m/e): 320(MH⁺).

7.3.103N2,N4-Bis[4-(ethoxycarbonylmethyleneoxy)phenyl]-5-cyano-2,4-pyrimidinediamine(R925775)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-cyanopyrimidine and ethyl 4-aminophenoxyacetatewerereacted to yieldN2,N4-bis[4-(ethoxycarbonylmethyleneoxy)phenyl]-5-cyano-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.80 (s, 1H), 7.40 (d, 4H, J=8.7 Hz), 6.90 (4H, J=9.0Hz), 6.82-6.75 (m, 2H). 4.60 (bs, 4H), 4.29-4.25 (m, 4H), 1.32-1.26 (m,5H), LCMS: ret. time: 28.50 min.; purity: 100%; MS (m/e): 493 (MH⁺).

7.3.104 R935192: N2,N4-Bis(1-methyl-indazolin-5-yl)-5-fluoro-2,4-pyrimidinediamine

In like manner to the preparation of N2, N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-5-fluoropyrimidine and 1-methyl-5-aminoindazole were reacted toproduce N2,N4-bis(1-methyl-indazolin-5-yl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(DMSO-d6): δ 10.65 (s, 1H), 10.41 (s, 1H), 8.29 (d, 1H, J=5.3 Hz), 7.98(s, 1H), 7.79 (d, 2H, J=9.4 Hz), 7.69-7.54 (m, 4H), 7.35 (dd, 1H, J=1.7and 9.4 Hz), 4.03 (s, 3H), 4.01 (s, 3H). LCMS: ret. time: 16.86 min.;purity: 99%; MS (m/e): 389 (MH⁺).

7.3.105 R935205: N2,N4-Bis[1-(methoxycarbonyl)methyl-indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamine

In like manner to the preparation of 5-fluoro-N2, N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrmidineand 6-amino-1-(methoxycarbonyl)methyl-indazoline were reacted to produceN2,N4-bis[1-(methoxycarbonyl)methyl-indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.59 (s, 1H), 9.45 (s, 1H), 8.18 (d, 1H, J=3.5 Hz),8.11 (s, 1H), 8.04 (s, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.69 (d, 1H,J=8.8 Hz), 7.58 (d, 1H, J=8.8 Hz), 7.48 (dd, 1H, J=1.7 and 8.8 Hz), 7.32(d, 1H, J=8.8 Hz), 5.17 (s, 2H), 4.88 (s, 1H), 3.58 (s, 3H), 3.58 (s,3H). LCMS: ret. time: 17.80 min.; purity: 99%; MS (m/e): 505 (MH⁺).

7.3.106 R935211: N2,N4-Bis[1-(methoxycarbonyl)methyl-indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrmidine and6-amino-1-(methoxycarbonyl)methyl-indazoline was reacted to produce N2,N4-bis[1-(methoxycarbonyl)methyl-indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.37 (s, 1H), 9.17 (s, 1H), 8.11-8.06 (m, 3H), 7.94(s, 1H), 7.70 (s, 1H), 7.63 (s, 2H), 7.46 (s, 2H), 5.40 (s, 2H), 5.31(s, 2H), 3.67 (s, 3H), 3.64 (s, 3H). LCMS: ret. time: 17.06 min.;purity: 96%; MS (m/e): 505 (MH⁺).

7.3.107 R935188:N2,N4-Bis(indazolin-6-yl)-5-fluoro-2,4-pyrimidinediamine

In like manner to the preparation of 5-fluoro-N2, N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2,4-dichlro-5-fluoropyrimidineand 6-aminoindazoline were reacted to produceN2,N4-bis(indazolin-6-yl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(DMSO-d6): δ 9.80 (s, 1H), 9.65 (s, 1H), 8.20 (d, 1H, J=4.1 Hz), 8.01(s, 1H), 7.96 (s, 1H), 7.93 (s, 1H), 7.89 (s, 1H), 7.69 (d, 1H, J=8.8Hz), 7.57 (d, 1H, J=8.3 Hz), 7.54 (dd, 1H, J=1.7 and 8.8 Hz), 7.29 (dd,1H, J=1.7 and 8.8 Hz); LCMS: ret. time:15.17 min.; purity: 94%; MS(m/e): 361 (MH⁺).

7.3.108 R935189: N2,N4-Bis(indazolin-5-yl)-5-fluoro-2,4-pyrimidinediamine

In like manner to the preparation of N2, N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 5-aminoindazole were reacted toproduce N2, N4-bis(indazolin-5-yl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (DMSO-d6): δ 10.05 (s, 1H), 9.76 (s, 1H), 8.16 (d, 1H, J=4.7 Hz),8.05 (s, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 7.52-7.52 (m,2H), 7.44 (d, 1H, J=8.8 Hz), 7.34 (dd, 1H, J=1.7 and 8.8 Hz); LCMS: ret.time: 14.33 min.; purity: 100%; MS (m/e): 361 (MH⁺).

7.3.109N2,N4-Bis(1-ethoxycarbonyl-2-methylpropyl)-5-cyano-2,4-pyrimidinediamine(R925814)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-cyanopyrimidine and valine ethyl ester were reacted toyieldN2,N4-bis(1-ethoxycarbonyl-2-methylpropyl)-5-cyano-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.15 (s, 1H), 6.10 (d, 1H, J=8.4 Hz), 5.67 (d, 1H,J=8.1 Hz), 4.66-4.62 (m, 1H), 4.50-4.46 (m, 1H), 4.25-4.13 (m, 4H),2.27-2.14 (m, 2H), 1.31-1.24 (m, 6H), 1.00-0.94 (m, 12H); LCMS: ret.time: 30.41 min.; purity: 98%; MS (m/e): 392 (MH⁺).

7.3.110N2,N4-Bis(1-methoxycarbonyl-3-methylbutyl)-5-cyano-2,4-pyrimidinediamine(R925815)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-cyanopyrimidine and leucine methyl ester were reacted toyieldN2,N4-bis(1-methoxycarbonyl-3-methylbutyl)-5-cyano-2,4-pyrimidinediamine.¹H NMR (CDCl₃): mixture of rotamers δ 8.15 (s, 1H), 6.10 and 5.49 (2d,1H, J=8.1 Hz), 5.53 (d, 1H, J=8.4 Hz), 4.80-4.67 (m, 1H), 4.57-4.48 (m,1H), 3.73 (s, 3H), 3.71 (s, 3H), 1.78-1.60 (m, 6H), 0.97-0.89 (m, 12H);LCMS: ret. time: 30.33 min.; purity: 91%; MS (m/e): 392 (MH⁺).

7.3.111 N2,N4-Bis(methoxycarbonylbenzyl)-5-cyano-2,4-pyrimidinediamine(R925819)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-cyanopyrimidine and phenyl glycine methyl ester werereacted to yieldN2,N4-bis(methoxycarbonylbenzyl)-5-cyano-2,4-pyrimidinediamine. ¹H NMR(CDCl₃): mixture of rotamers δ 8.15 (s, 1H), 7.69-7.60 (m, 1H),7.42-7.32 (m, 10H), 6.20 and 5.73 (2d, 1H, J=6.6 Hz), 6.14 and 5.65 (2d,1H, J=6.3 Hz), 5.55 (d, 1H, J=6.3 Hz), 5.39 (t, 1H, J=7.2 Hz), 3.79 and3.78 (2s, 3H), 3.67 and 3.65 (2s, 3H); LCMS: ret. time: 30.22 min.;purity: 91%; MS (m/e): 432 (MH⁺).

7.3.112N2,N4-Bis[4-(ethoxycarbonylmethyl)phenyl]-5-cyano-2,4-pyrimidinediamine(R926662)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-cyanopyrimidine and ethyl 4-aminophenylacetate werereacted to yieldN2,N4-bis[4-(ethoxycarbonylmethyl)phenyl]-5-cyano-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.29 (bs, 1H), 7.46 (2d, 4H, J=7.8 Hz), 7.28 (d, 2 h,J=8.1 Hz), 7.19 (d, 2H, J=8.1 Hz), 4.16 (2q, 4H, J=6.3 Hz), 3.64 (s,2H), 3.59 (s, 2H), 1.30-1.23 (m, 6H); LCMS: ret. time: 29.29 min.;purity: 93%; MS (m/e): 461 (MH⁺).

7.3.113 R935000:N2,N4-Bis(2-methoxy-5-phenylphenyl)-5-methyl-2,4-pyrimidinediamine

In like manner to the preparation of5-fluoro-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine,5-phenyl-2-anisidine and 2,4-dichloro-5-methylpyrimidine were reacted toprovideN2,N4-bis(2-methoxy-5-phenylphenyl)-5-methyl-2,4-pyrimidinediamine. ¹HNMR (CDCl₃+CD₃OD): δ 7.76 (d, 1H, J=2.3 Hz), 7.57 (s, 1H), 7.56 (s, 1H),7.02-6.85 (m, 8H), 6.86-6.80 (m, 4H), 6.72 (d, 2H), 3.73 (s, 3H), 3.72(s, 3H), 2.07 (s, 3H); LCMS: ret. time: 31.53 min.; purity: 97%; MS(m/e): 489 (MH⁺).

7.3.114 R935001:N2,N4-Bis[(2-methyl-5-phenyl)phenyl]-5-methyl-2,4-pyrimidinediamine

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-phenyl-2-toluidine and 2,4-dichloro-5-methylpyrimidine were reacted toproduceN2,N4-bis[(2-methyl-5-phenyl)phenyl]-5-methyl-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ 7.59-7.55 (m, 1H), 7.45 (d, 2H, J=3.6 Hz), 7.26-7.17 (m,6H), 7.09-6.98 (m, 8H), 2.36 (s, 3H), 2.22 (s, 3H), 2.21 (s, 3H); LCMS:ret. time: 32.44 min.; purity: 90%; MS (m/e): 457 (MH⁺).

7.3.115 R935002:N2,N4-Bis[(4-methoxy-3-phenyl)phenyl]-5-methyl-2,4-pyrimidinediamine

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,3-phenyl-4-anisidine hydrochloride and 2,4-dichloro-5-methylpyrimidinewith an added diisopropylethylamine were reacted to produceN2,N4-bis[(4-methoxy-3-phenyl)phenyl]-5-methyl-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ 8.15 (d, 1H, J=2.3 Hz), 7.76 (t, 1H, J=2.3 Hz), 7.71 (s,1H), 7.59 (s, 1H), 7.16-7.03 (m, 8H), 6.98-6.81 (5H), 3.96 (s, 3H), 3.89(s, 3H), 2.21 (s, 3H); LCMS: ret. time: 32.01 min.; purity: 90%; MS(m/e): 489 (MH⁺).

7.3.116 R935003:N2,N4-Bis[(4-phenyl-2-methoxy-5-methyl)phenyl]-5-methyl-2,4-pyrimidinediamine

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-methyl-4-phenyl-2-anisidine and 2,4-dichloro-5-methylpyrimidine werereacted to produceN2,N4-bis[(4-phenyl-2-methoxy-5-methyl)phenyl]-5-methyl-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 9.25 (br s, 1H), 8.17 (s, 1H), 7.77 (t, 1H, J=6.4 Hz),7.66 (s, 2H), 7.43-7.25 (m, 10H), 6.79 (s, 2H), 3.91 (s, 3H), 3.85 (s,3H), 2.20 (s, 3H), 2.09 (s, 3H), 2.02 (s, 3H); LCMS: ret. time: 31.10min.; purity: 100%; MS (m/e): 517 (MH⁺).

7.3.117 R935004:N2,N4-Bis[[di-(4-methoxyphenyl)]methyl]-5-fluoro-2,4-pyrimidinediamine

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,1,1-di(4-anisyl)methylamine and 2,4-dichloro-5-fluoropyrimidine werereacted to produceN2,N4-bis[[di-(4-methoxyphenyl)]methyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃+CD₃OD): δ 7.91 (d, 1H, J=2.3 Hz), 7.18 (d, 8H, J=9.0 Hz),6.85 (d, 8H, J=9.0 Hz), 6.40 (d, 1H, J=8.2 Hz), 5.39 (d, 1H, J=7.1 Hz),3.81 (s, 6H), 3.78 (s, 6H); LCMS: ret. time: 32.76 min.; purity: 95%; MS(m/e): 581 (MH⁺).

7.3.118 R935005:N2,N4-Bis(diphenylmethyl)-5-fluoro-2,4-pyrimidinediamine

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 1,1-diphenylmethylamine and 2,4-dichloro-5-fluoropyrimidine were reacted to produceN2, N4-bis(diphenylmethyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CDCl₃): δ 7.91 (d, 1H, J=2.3 Hz), 7.39-7.25 (m, 20H), 6.51 (d, 1H,J=8.2 Hz), 5.77 (d, 1H, J=7.0 Hz); LCMS: ret. time: 33.46 min.; purity:92%; MS (m/e): 461 (MH⁺).

7.3.119 R935006:N2,N4-Bis[di-(4-chlorophenyl)methyl]-5-fluoro-2,4-pyrimidinediamine

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,benzhydrylamine and 2,4-dichloro-5-fluoropyrimidine were reacted toyieldN2,N4-bis[di-(4-chlorophenyl)methyl]-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃+CD₃OD): δ 7.94 (d, 1H, J=2.3 Hz), 7.40-7.20 (m, 16H), 6.46(d, 1H, J=8.2 Hz), 5.69 (d, 1H, J=7.0 Hz); LCMS: ret. time: 32.83 min.;purity: 90%; MS (m/e): 599 (MH⁺).

7.3.120 R935016:N2,N4-Bis[1(R)-4-methoxyphenylethyl]-5-bromo-2,4-pyrimidineamine

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,(R)-(+)-1-(4-methoxyphenyl)ethylamine and 5-bromo-2,4-dichloropyrimidinewere reacted to produce N2,N4-bis[1(R)-4-methoxyphenylethyl]-5-bromo-2,4-pyrimidineamine. ¹H NMR (CDCl₃): δ7.81 (s, 1H), 7.25 (d, 4H, J=8.4 Hz), 6.86 (app t, 4H, J=8.4 and 8.7Hz), 5.27-5.20 m (2H), 5.09 (dq, 1H, J=6.4 and 7.0 Hz), 4.89 (dq, 1H,J=6.4 and 7.0 Hz), 3.80 (s, 3H), 3.79 (s, 3H), 1.40 (d, 6H, J=7.0 Hz).

7.3.121 R935075: N2,N4-Bis[3-(2-hydroxyethoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-(3-aminophenoxy)ethanol werereacted to produceN2,N4-bis[3-(2-hydroxyethoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (DMSO-d6): δ 9.50 (br s, 1H), 9.35 (br s, 1H), 8.13 (d, 1H, J=4.1Hz), 7.44 (d, 1H, J=7.6 Hz), 7.26-7.19 (m, 4H), 7.10 (t, 1H, J=7.6 Hz),6.65 (dd, 1H, J=2.3 and 8.2 Hz), 6.50 (dd, 1H, J=2.3 and 8.2 Hz), 5.0(br s, 2H), 3.91 (t, 2H, J=5.2 Hz), 3.85 (t, 2H, J=5.2 Hz), 3.68 (qt,2H, J=5.2 Hz), 3.66 (qt, 2H, J=5.2 Hz); LCMS: ret. time: 15.76 min.;purity: 97%; MS (m/e): 401 (MH⁺).

7.3.122 R935076:N2,N4-Bis[3-(2-methoxyethyl)oxyphenyl]-5-fluoro-2,4-pyrimidinediamine

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-(2-methoxyethoxy)aniline werereacted to produceN2,N4-bis[3-(2-methoxyethyl)oxyphenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.96 (d, 1H, J=2.9 Hz), 7.36 (t, 1H, J=1.7 Hz), 7.28(t, 1H J=1.7 Hz), 7.25-7.06 (m, 4H), 6.98 (br s, 1H), 6.75 (d, 1H, J=2.3Hz), 6.70 (dd, 1H, J=1.7 and 8.2 Hz), 6.58 (dd, 1H, J=1.7 and 8.2 Hz),4.08-4.03 (m, 4H), 3.74-3.69 (m, 4H), 3.44 (s, 3H), 3.43 (s, 3H); LCMS:ret. time: 21.01 min.; purity: 97%; MS (m/e): 429 (MH⁺).

7.3.123 R935077:N2,N4-Bis(5-hydroxy-2-isopropylphenyl)-5-fluoro-2,4-pyrimidinediamine

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,3-amino-4-isopropylphenol and 2,4-dichloro-5-fluoropyrimidine werereacted to produceN2,N4-bis(5-hydroxy-2-isopropylphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.93 (d, 1H, J=3.5 Hz), 7.79 (br s, 1H), 7.64 (br s,1H), 7.13 (d, 1H, J=8.7 Hz), 7.06 (d, 1H, J=2.3 Hz), 7.05 (d, 1H, J=8.7Hz), 6.89 (d, 1H, J=2.3 Hz), 6.66 (d, 1H, J=2.3 and 8.7 Hz), 6.57 (d,1H, J=2.3 and 8.7 Hz), 2.96 (m, 2H), 1.25 (d, 6H, J=7.0 Hz), 1.13 (dd,6H, J=7.0 Hz); LCMS: ret. time: 24.27 min.; purity: 97%; MS (m/e): 397(MH⁺).

7.3.124 R935114:N2,N4-Bis(3-methoxycarbonylmethylenephenyl)-5-fluoro-2,4-pyrimidinediamine

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-(methoxycarbonylmethylene)anilinewere reacted to produce the desiredN2,N4-bis(3-methoxycarbonylmethylenephenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.23 (br s, 1H), 10.05 (br s, 1H), 8.26 (d, 1H,J=4.6 Hz), 7.64 (d, 1H, J=8.2 Hz), 7.51 (br s, 1H), 7.46 (d, 1H, J=8.2Hz), 7.33 (br s, 1H), 7.29 (t, 1H, J=7.6 Hz), 7.20 (t, 1H, J=7.6 Hz),7.06 (d, 1H, J=7.6 Hz), 6.93 (d, 1H, J=7.6 Hz), 3.63 (s, 2H), 3.58 (s,3H), 3.57 (s, 3H), 3.56 (s, 2H); LCMS: ret. time: 21.74 min.; purity:92%; MS (m/e): 425 (MH⁺).

7.3.125 R935162: N2,N4-Bis(3,4-propylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and (3,4-propylenedioxy)aniline werereacted to giveN2,N4-bis(3,4-propylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (DMSO-d6): δ 9.18 (s, 1H), 9.07 (s, 1H), 8.03 (d, 1H, J=3.5 Hz),7.38 (dd, 1H, J=2.3 and 8.2 Hz), 7.35 (d, 1H, J=2.3 Hz), 7.33 (d, 1H,J=2.3 Hz), 7.18 (dd, 1H, J=2.3 and 8.8 Hz), 6.90 (d, 1H, J=8.8 Hz), 6.80(d, 1H, J=8.2 Hz), 4.11-3.98 (m, 8H), 2.09-2.01 (m, 4H); LCMS: ret.time: 21.40 min.; purity: 97%; MS (m/e): 425 (MH⁺).

7.3.126 R935163: N2,N4-Bis(3-chloro-4-fluoropheny)-2,4-pyrimidinediamine

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-fluoroaniline werereacted to produce N2,N4-bis(3-chloro-4-fluoropheny)-2,4-pyrimidinediamine. ¹H NMR (DMSO-d6):δ 9.58 (s, 1H), 9.48 (s, 1H), 8.17 (d, 1H, J=4.1 Hz), 7.94-7.90 (m, 2H),7.73-7.67 (m, 1H), 7.51-7.45 (m, 1H), 7.38 (t, 1H, J=8.8 Hz), 7.26 (t,1H, J=8.8 Hz); LCMS: ret. time: 27.83 min.; purity: 99%; MS (m/e): 386(MH⁺).

7.3.127N2,N4-Bis(3-hydroxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine(R925849)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-6-ethoxycarbonyl-5-nitropyrimidine and 3-aminophenol werereacted to yieldN2,N4-bis(3-hydroxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.56 (bs, 1H), 10.32 (bs, 1H), 9.54 (s, 1H), 9.32(bs, 1H), 7.22-7.15 (m, 2H), 7.02-6.96 (m, 1H), 6.93-6.82 (m, 2H),6.81-6.74 (m, 1H), 6.67 (d, 1H, J=9.3 Hz), 6.43 (d, 1H, J=8.1 Hz), 4.35(q, 2H, J=6.9 Hz), 1.30 (t, 3H, J=6.9 Hz); LCMS: ret. time: 26.01 min.;purity: 96%; MS (m/e): 412 (MH⁺).

7.3.128N2,N4-Bis(3,4-ethylendioxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine(R925852)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-6-ethoxycarbonyl-5-nitropyrimidine and3,4-ethylenedioxyaniline were reacted to yieldN2,N4-bis(3,4-ethylendioxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.52 (s, 1H), 10.28 (s, 1H), 7.07-7.01 (m, 2H),6.96 (dd, 1H, J=1.8 and 8.7 Hz), 6.90-6.84 (m, 2H), 6.61 (d, 1H, J=8.7Hz), 4.33 (q, 2H, J=6.9 Hz), 4.24 (s, 4H), 4.17 (s, 4H), 1.29 (t, 3H,J=6.9 Hz); LCMS: ret. time: 30.40 min.; purity: 100%; MS (m/e): 496(MH⁺).

7.3.129N2,N4-Bis(ethoxycarbonylmethyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine(R925864)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, with theaddition of triethylamine,2,4-dichloro-6-ethoxycarbonyl-5-nitropyrimidine and glycine ethyl esterhydrochloride were reacted to yieldN2,N4-bis(ethoxycarbonylmethyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): mixture of rotamers δ 8.99 and 8.80 (2bs, 1H), 6.22 and6.00 (2bs, 1H), 4.45 (t, 2H, J=7.2 Hz), 4.31-4.21 (m, 6H), 4.14 (d, 2H,J=5.1 Hz), 1.39 (t, 3H, J=7.2 Hz), 1.34-1.28 (m, 6H); LCMS: ret. time:26.06 min.; purity: 99%; MS (m/e): 400 (MH⁺).

7.3.130 N2,N4-Bis[2-(4-hydroxyphenyl)ethyl]-2,4-pyrimidinediamine(R925790)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and tyramine were reacted to yieldN2,N4-bis[2-(4-hydroxyphenyl)ethyl]-2,4-pyrimidinediamine. ¹H NMR(DMSO-d6): δ 11.56 (bs, 1H), 9.23 (s, 1H), 8.89 (bs, 1H), 7.92 (bs, 1H),7.60 (d, 1H, J=6.9 Hz), 6.99 (d, 4H, J=8.1 Hz), 6.65 (d, 4H, J=8.1 Hz),6.00 (d, 1H, J=7.2 Hz), 3.59-3.42 (m, 4H), 2.76-2.67 (m, 4H); LCMS: ret.time: 17.93 min.; purity: 95%; MS (m/e): 351 (MH⁺).

7.3.131 N2,N4-Bis(2-phenylphenyl)-2,4-pyrimidinediamine (R925804)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 2-aminobiphenyl were reacted to yieldN2,N4-bis(2-phenylphenyl)-2,4-pyrimidinediamine. ¹H NMR (CDCl₃): δ 8.36(d, 1H, J=8.1 Hz), 7.97 (d, 1H, J=5.7 Hz), 7.80 (d, 1H, J=7.5 Hz),7.50-7.21 (m, 15H), 7.12-7.05 (m, 1H), 6.91 (bs, 1H), 6.38 (bs, 1H),6.07 (d, 1H, J=6.0 Hz); LCMS: ret. time: 29.94 min.; purity: 100%; MS(m/e): 415 (MH⁺).

7.3.132 N2,N4-Bis(2-methoxy-5-phenylphenyl)-2,4-pyrimidinediamine(R925805)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 5-phenyl-ortho-anisidine were reacted toyield N2,N4-bis(2-methoxy-5-phenylphenyl)-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ 7.88-7.84 (m, 2H), 7.82 (d, 1H, J=6.9 Hz), 7.30-7.14 (m,14H), 7.10 (dd, 2H, J=3.0 and 8.1 Hz), 6.48 (d, 1H, J=6.9 Hz), 3.93 (s,3H), 3.92 (s, 3H); LCMS: ret. time: 30.09 min.; purity: 94%; MS (m/e):476 (MH⁺).

7.3.133N2,N4-Bis(3-carboxy-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945041)

In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, from5-amino-2-hydroxybenzoic acid (458 mg, 3 mmol) and2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gaveN2,N4-bis(3-carboxy-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (235mg, 98%). ¹H NMR (DMSO-d6): δ 6.76 (d, J=9.0 Hz, 1H), 6.88 (d, J=9.6 Hz,1H), 7.75 (dd, J=3.0, 9.0 Hz, 1H), 7.90-7.94 (m, 3H), 8.02 (d, J=3.9 Hz,1H), 9.04 (s, 1H, NH), 9.28 (s, 1H, NH); ¹⁹F NMR (282 MHz, DMSO-d6): δ−165.79; LC: 16.02 min, 86.82%; MS (m/z): 400.94 (MH⁺).

7.3.134 N2,N4-Bis(4-methoxy-3-phenylphenyl)-2,4-pyrimidinediamine(R925806)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, with theaddition of triethylamine, 2,4-dichloropyrimidine and3-phenyl-para-anisidine hydrochloride were reacted to yieldN2,N4-bis(4-methoxy-3-phenylphenyl)-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ 7.93 (d, 1H, J=2.4 Hz), 7.88 (d, 1H, J=2.4 Hz), 7.29 (dd, 1H,J=1.8 and 9.0 Hz), 7.26-7.18 (m, 13H), 7.10 (d, 2H, J=8.7 Hz), 6.46 (d,1H, J=7.2 Hz), 3.93 (s, 3H), 3.92 (s, 3H); LCMS: ret. time: 29.99 min.;purity: 92%; MS (m/e): 476 (MH⁺).

7.3.135 N2,N4-Bis(2-methyl-5-phenylphenyl)-2,4-pyrimidinediamine(R925807)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 5-phenyl-ortho-toluidine were reacted toyield N2,N4-bis(2-methyl-5-phenylphenyl)-2,4-pyrimidinediamine. ¹H NMR(DMSO-d6): δ 10.45 (bs, 1H), 10.01 (bs, 1H), 7.86 (bs, 1H), 7.69-7.22(m, 17H), 2.28 (s, 6H); LCMS: ret. time: 18.69 min.; purity: 98%; MS(m/e): 443 (MH⁺).

7.3.136N2,N4-Bis(2-methoxy-5-methyl-4-phenylphenyl)-2,4-pyrimidinediamine(R925808)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 5-methyl-4-phenyl-ortho-anisidine werereacted to yieldN2,N4-bis(2-methoxy-5-methyl-4-phenylphenyl)-2,4-pyrimidinediamine. ¹HNMR (DMSO-d6): δ 9.99 (bs, 1H), 9.22 (bs, 1H), 7.98 (d, 1H, J=6.3 Hz),7.75 (s, 1H), 7.59 (s, 1H), 7.46-7.29 (m, 10H), 6.92 (s, 1H), 6.87 (s,1H), 6.49 (d, 1H, J=5.4 Hz), 3.82 (s, 3H), 3.81 (s, 3H), 2.07 (s, 3H),1.98 (s, 3H); LCMS: ret. time: 19.69 min.; purity: 93%; MS (m/e): 503(MH⁺).

7.3.137N2,N4-Bis[4-(ethoxycarbonylmethyleneoxy)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine(R925862)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-trifluoromethylpyrimidine and ethyl 4-aminophenoxyacetatewere reacted to yieldN2,N4-bis[4-(ethoxycarbonylmethyleneoxy)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.64 (bs, 1H), 8.80 (bs, 1H), 8.29 (s, 1H), 7.36 (d,2H, J=8.1 Hz), 7.31 (d, 2H, J=9.3 Hz), 6.93 (d, 2H, J=8.7 Hz), 6.70 (d,2H, J=9.0 Hz), 4.80 (s, 2H), 4.67 (s, 2H), 4.18 (q, 2H, J=6.9 Hz), 4.15(q, 2H, J=6.9 Hz), 1.20 (t, 3H, J=6.9 Hz), 1.19 (t, 3H, J=6.9 Hz); ¹⁹FNMR (DMSO-d6): −16932; LCMS: ret. time: 26.33 min.; purity: 98%; MS(m/e): 535 (MH⁺).

7.3.138N2,N4-Bis(3-hydroxyphenyl)-5-trifluoromethyl-2,4-pyrimidinediamine(R925863)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-trifluoromethylpyrimidine and 3-aminophenol were reactedto yieldN2,N4-bis(3-hydroxyphenyl)-5-trifluoromethyl-2,4-pyrimidinediamine. ¹HNMR (DMSO-d6): δ 9.82 (bs, 1H), 8.88 (bs, 1H), 8.36 (s, 1H), 7.18-7.11(m, 2H), 6.96 (m, 4H), 6.63 (dd, 1H, J=2.4 and 8.1 Hz), 6.38 (d, 1H,J=8.1 Hz); ¹⁹F NMR (DMSO-d6): −16979; LCMS: ret. time: 19.04 min.;purity: 95%; MS (m/e): 363 (MH⁺).

7.3.139N2,N4-Bis[4-(ethoxycarbonylmethyl)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine(R926663)

In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-trifluoromethylpyrimidine and ethyl 4-aminophenylacetatewere reacted to yieldN2,N4-bis[4-(ethoxycarbonylmethyl)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.31 (s, 1H), 7.46 (d, 2H, J=9.0 Hz), 7.45 (d, 2H,J=8.7 Hz), 7.30 (d, 2H, J=9.0 Hz), 7.18 (d, 2H, J=8.7 Hz), 7.16 (bs,1H), 6.82 (bs, 1H), 4.16 (2q, 4H, J=7.8 Hz), 3.64 (s, 2H), 3.57 (s, 2H),1.27 (t, 3H, J=7.8 Hz), 1.26 (t, 3H, J=7.8 Hz); ¹⁹F NMR (CDCl₃): −17223;LCMS: ret. time: 28.07 min.; purity: 99%; MS (m/e): 504 (MH⁺).

7.3.140N2,N4-Bis(2,5-dimethyl-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926623)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2,5-dimethyl-4-hydroxyaniline werereacted to yieldN2,N4-bis(2,5-dimethyl-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.63 (d, 1H, J=4.2 Hz), 7.05 (s, 1H), 6.97 (s, 1H),6.64 (1H), 6.54 (s, 1H), 2.12 (s, 6H), 2.06 (s, 3H), 2.03 (s, 3H), 2.03(s, 3H); ¹⁹F NMR (CD₃OD): −48488; LCMS: ret. time: 18.28; purity; 94%;MS (m/e): 369 (MH⁺).

7.3.141 N2,N4-Bis(3-sodiumphenoxy)-5-fluoro-2,4-pyrimidinediamine(R926461)

The reaction ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine with 2equivalents of sodium methoxide in methanol followed by removal ofsolvent gave the requisite compound,N2,N4-bis(3-sodiumphenoxy)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR (D₂O):δ 7.65 (bd, 1H), 7.00-6.90 (m, 2H), 6.71 (m, 2H), 6.55 (dd, 1H, J=1.2and 6.3 Hz), 6.31 (bd, 1H, J=8.1 Hz), 6.23 (bd, 1H, J=8.7 Hz); ¹⁹F NMR(D₂O): −47016; LCMS: ret. time: 15.68 min.; purity: 99%; MS (m/e): 313(MH⁺).

7.3.142 N2,N4-Bis(3-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine(R945051)

In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,3-aminobenzonitrile (177 mg, 1.5 mmol) and2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gaveN2,N4-bis(3-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine (75 mg, 76%). ¹HNMR (acetone-d₆): δ 7.33 (dt, J=1.8, 7.8 Hz, 1H), 7.46-7.52 (m, 2H),7.59 (t, J=7.8 Hz, 1H), 7.90 (ddd, J=0.9, 2.1 and 8.4 Hz, 1H), 8.09(ddd, J=1.2, 2.4 and 8.4 Hz, 1H), 8.17 (d, J=3.3 Hz, 1H), 8.31 (m, 1H),8.35 (t, J=2.1 Hz, 1H), 8.98 (br, 1H, NH), 9.02 (br, 1H, NH); ¹⁹F NMR(282 MHz, acetone-d₆): δ −165.80; LCMS: 24.64 min.; purity: 98.02%; MS(m/e): 331.01 (MH⁺).

7.3.143N2,N4-Bis(benzothiophen-3-ylmethyl)-5-fluoro-2,4-pyrimidinediamine(R945145)

Using procedure similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,benzothiophen-3-ylmethylamine and 2,4-dichloro-5-fluoropyrimidine gaveN2,N4-bis(benzothiophen-3-ylmethyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ 4.82 (dd, J=0.9 and 5.7 Hz, 2H), 4.86 (dd, J=0.9 and 5.7Hz, 2H), 5.14 (br, 2H), 7.31-7.40 (m, 6H), 7.75-7.89 (m, 5H); ¹⁹F NMR(282 MHz, CDCl₃): δ −172.12; LCMS: 27.79 min.; purity: 96.47%; MS (m/e):420.92 (MH⁺).

7.3.144N2,N4-Bis[4-(N-benzylpiperazino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R945152)

In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 4-(N-benzylpiperazino)aniline (400 mg, 1.5 mmol) and2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) resultedN2,N4-bis[4-(N-benzylpiperazino)phenyl]-5-fluoro-2,4-pyrimidinediamine(120 mg, 64%). ¹H NMR (CDCl₃): δ 2.63 (p, J=2.4 Hz, 8H), 3.14 (t, J=4.8Hz, 4H), 3.19 (t, J=4.8 Hz, 4H), 3.58 (s, 4H), 6.58 (d, 1H, NH), 6.67(br, 1H, NH), 6.87 (d, J=9.3 Hz, 2H), 6.90 (d, J=9.0 Hz, 2H), 7.33-7.39(m, 12H), 7.46 (d, J=9.0 Hz, 2H), 7.87 (d, J=3.3 Hz, 1H); ¹⁹F NMR (282MHz, CDCl₃): δ −169.06; LCMS: 16.82 min.; purity: 96.88%; MS (m/e):629.12 (MH⁺).

7.3.145N2,N4-Bis(3-hydroxy-2-methylphenyl)-5-fluoro-2,4-pyrimidinediamine(R945038)

In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 3-hydroxy-2-methylaniline (369 mg, 3 mmol) and2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gaveN2,N4-bis(3-hydroxy-2-methylphenyl)-5-fluoro-2,4-pyrimidinediamine (180mg, 88%). ¹H NMR (acetone-d₆): δ 2.14 (s, 3H), 2.22 (s, 3H), 6.61 (d,J=8.1 Hz, 1H), 6.78 (t, J=8.7 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 6.99 (d,J=9.0 Hz, 1H), 7.08 (t, J=7.8 Hz, 1H), 7.13 (dd, J=3.9, 8.4 Hz, 1H),8.24 (d, J=5.1 Hz, 1H), 8.32 (br, 1H, NH), 8.57 (br, 1H, NH); LCMS: ret.time: 16.51 min.; purity: 90.47%; MS (m/e): 341.07 (MH⁺).

7.3.146 N2,N4-Bis(3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine(R950160)

2,4-Dichloro-5-fluoropyrimidine (4.7 g, 28.1 mmol) was dissolved in amixture of MeOH (150 ml) and H₂O (15 ml). 3-nitroaniline (15.5 g, 112mmol) was added and the mixture was refluxed for 20 hours (100° C.oil-bath temperature). The mixture was cooled to 22° C. and filtered.The residue was washed carefully with 200 ml MeOH—H₂O (1:1; v/v) anddried under vacuum to give 7.89 g (76%) ofN2,N4-bis(3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine as yellowcrystals. ¹H NMR (DMSO-d6+D₂O): δ 8.63 (m, 2H), 8.21 (m, 1H), 8.08 (d,1H, J=8.41 Hz), 7.88 (d, 1H, J=8.4 Hz), 7.79 (d, 1H, J=8.4 Hz), 7.70 (d,1H, J=8.4 Hz), 7.57 (d, 1H, J=8.4 Hz), 7.45 (t, 1H, J=8.4 Hz); LCMS:purity: 100%; MS (m/e): 371.30 (M⁺, 100).

7.3.147 N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine(R921302)

N2,N4-Bis(3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine (4.0 g, 10.8mmol) and Pd/C 10% (1.2 g, 50% water content) were suspended in 300 mlEtOH-10% aqueous HCl (1:1) and hydrogenated in a Parr apparatus for 6hours (22° C., 50 psi). The suspension was filtered over celite andcarefully washed with 20 ml DMF-H₂O (1:1; v/v) followed by 50 ml H₂O.The combined filtrates were concentrated under reduced pressure to givepale yellow oil, which was triturated with MeOH to give the product asfine white needles. The precipitate was filtered off and washed withMeOH followed by Et₂O. The remaining crystals were dried under vacuum togive 4.00 g of pure material (100%) as determined by LCMS. The freeamine was obtained by adding 10 ml 1 N NaOH to a solution of Ig HCl-saltin 5 ml H₂O. The resulting precipitate was filtered, washed with H₂O anddried under vacuum for 24 hours to giveN2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine (770 mg) as awhite solid. ¹H NMR (CD₃OD): δ 7.92 (d, 1H, J=3.6 Hz), 7.31 (t, 1H,J=2.1 Hz), 7.21 (t, 1H, J=2.4 Hz), 7.08, (t, 1H, J=8.1 Hz), 6.99 (t, 1H,J=8.1 Hz), 6.88 (m, 1H), 6.77 (m, 1H), 6.47 (m, 1H), 6.34 (m, 1H); LCMS:purity: 100%; MS (m/e): 311.07 (M⁺, 100).

7.3.148 N2,N4-Bis(4-aminophenyl)-5-fluoro-2,4-pyrimidinediamine(R950122)

In like manner to the preparation ofN2,N4-bis(3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 1,4-diaminobenzene were reacted toprepare N2,N4-bis(4-aminophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 11.15 min.; purity: 100%; MS (m/e): 311.09 (MH⁺).

7.3.149N2,N4-Bis[3-(dimethylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R950182)

2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) was dissolved in amixture of MeOH (0.3 ml) and H₂O (0.03 ml). N,N-3-dimethyldiaminoaniline(163 mg, 1.2 mmol) was added and the mixture was refluxed for 24 hours(70° C. oil-bath temperature). The mixture was cooled to 22° C.,concentrated to dryness under reduced pressure and subjected to columnchromatography on silica gel (CHCl₃-Acetone, 2:1) to giveN2,N4-bis[3-(dimethylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine. LCMSpurity: 99.0%; MS (m/e): 367.13 (M⁺, 100).

7.3.150 N2,N4-Bis(3-amino-4-methylphenyl)-2,4-pyrimidinediamine(R950130)

2,4-Dichloropyrimidine (45 mg, 0.30 mmol) was dissolved in a mixture ofMeOH (1 ml) and H₂O (0.1 ml). 3-amino-4-methylaniline (146 mg, 1.2 mmol)was added and the mixture was refluxed for 20 hours (70° C. oil-bathtemperature). The mixture was cooled to 22° C., concentrated to drynessunder reduced pressure and subjected to column chromatography on silicagel (CHCl₃-Acetone, 2:1) to giveN2,N4-bis(3-amino-4-methylphenyl)-2,4-pyrimidinediamine. ¹H NMR (CD₃OD):δ 8.13 (s, 1H), 6.95 (d, 2H, J=7.5 Hz), 6.82 (d, 2H, J=1.8 Hz), 6.60(dd, 2H, J=1.8, 7.5 Hz), 6.17 (s, 1H), 2.12 (s, 6H); LCMS purity: 97.3%;MS (m/e): 321.09 (M⁺, 100).

7.3.151 N2,N4-Bis(3-amino-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine(R950129)

2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) was dissolved in amixture of MeOH (1 ml) and H₂O (0.1 ml). 3-amino-4-methylaniline (146mg, 1.2 mmol) was added and the mixture was refluxed for 20 hours (70°C. oil-bath temperature). The mixture was cooled to 22° C., concentratedto dryness under reduced pressure and subjected to column chromatographyon silica gel (CHCl₃-Acetone, 2:1) to giveN2,N4-bis(3-amino-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ 8.11 (d, 1H, J=5.1 Hz), 7.98 (bs, 1H) (7.68 (dd, 1H, J=2.4,8.1 Hz), 7.40-7.55 (m, 4H), 2.43 (s, 3H), 2.42 (s, 3H); LCMS: purity:95.0%; MS (m/e): 338.66 (M⁺, 70).

7.3.152N2,N4-Bis[(4-methylsulfonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R950083)

2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) was dissolved in amixture of MeOH (1 ml) and H₂O (0.1 ml). 4-methylsulfonylaminoaniline(335 mg, 1.8 mmol) was added and the mixture was refluxed for 24 hours(100° C. oil-bath temperature). The mixture was cooled to 22° C. andfiltered. The residue was washed carefully with MeOH—H₂O (1:1) and driedunder vacuum to giveN2,N4-bis[(4-methylsulfonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.86 (s, 1H), 8.65 (s, 1H), 8.53 (bs, 1H), 8.39 (bs,1H), 7.32 (d, 1H, J=3.3 Hz), 7.12 (d, 1H, J=8.7 Hz), 6.98 (d, 1H, J=8.7Hz), 6.62 (d, 1H, J=8.7 Hz), 6.52 (d, 1H, J=8.7 Hz), 2.32 (s, 3H), 2.27(s, 3H); LCMS: purity: 96.8%; MS (m/e): 466.94 (M⁺, 100).

7.3.153N2,N4-Bis(4-benzyloxy-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine(R950090)

2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) was dissolved in amixture of MeOH (1 ml) and H₂O (0.1 ml).4-benzyloxy-3-trifluoromethylaniline (481 mg, 1.8 mmol) was added andthe mixture was refluxed for 2 days (70° C. oil-bath temperature). Themixture was cooled to 22° C., concentrated to dryness under reducedpressure and subjected to column chromatography on silica gel(CHCl₃-Acetone, 9:1) to giveN2,N4-bis(4-benzyloxy-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.51 (s, 1H), 8.05 (s, 1H), 7.38-7.64 (m, 5H),6.94-7.14 (m, 11H), 6.44-6.73 (m, 4H), 4.84 (s, 2H), 4.79 (s, 2H); LCMSpurity: 94.7%; MS (m/e): 628.93 (M⁺, 100).

7.3.154N2,N4-Bis(3-cyano-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950092)

2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) was dissolved in amixture of MeOH (1 ml) and H₂O (0.1 ml). 3-cyano-4-hydroxyaniline (241mg, 1.8 mmol) was added and the mixture was refluxed for 2 days (70° C.oil-bath temperature). The mixture was cooled to 22° C., concentrated todryness under reduced pressure and subjected to column chromatography onsilica gel (CHCl₃-Acetone, 9:1) to giveN2,N4-bis(4-hydroxy-3-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ 7.96 (d, 1H, J=3.5 Hz), 7.82 (d, 1H, J=3.0 Hz), 7.79 (d,1H, J=3.0 Hz), 7.71 (dd, 1H, J=3.0, 8.8 Hz), 7.54 (dd, J=3.0, 8.8 Hz),6.94 (d, 1H, J=8.8 Hz), 6.84 (d, 1H, J=8.8 Hz); LCMS: purity: 97.2%; MS(m/e): 362.98 (M⁺, 100).

7.3.155N2,N4-Bis[3-methylsulfonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R950100)

2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) was dissolved in amixture of MeOH (1 ml) and H₂O (0.1 ml). 3-methylsulfonylaminoaniline(300 mg, 1.5 mmol) was added and the mixture was refluxed for 24 hours(70° C. oil-bath temperature). The mixture was cooled to 22° C.,concentrated to dryness under reduced pressure and subjected to columnchromatography on silica gel (CHCl₃-Acetone, 9:1) to giveN2,N4-bis[3-methylsulfonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6+CD₃OD): δ 8.01 (d, 1H, J=3.5 Hz), 7.46-7.68 (m, 4H),7.49 (t, 1H, J=8.2 Hz), 7.13 (t, 1H, J=8.2 Hz), 6.89 (dd, 1H, J=2.4, 8.2Hz), 6.72 (m, 1H), 2.95 (s, 3H), 2.91 (s, 3H); LCMS: purity: 97.2%; MS(m/e): 466.89 (M⁺, 100).

7.3.156N2,N4-Bis[3-(tert-butoxycarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R950108)

2,4-Dichloro-5-fluoropyrimidine (75 mg, 0.45 mmol) was dissolved in amixture of MeOH (2 ml) and H₂O (0.2 ml).3-tert-butoxycarbonylaminoaniline (374 mg, 1.8 mmol) was added and themixture was refluxed for 40 hours (70° C. oil-bath temperature). Themixture was cooled to 22° C., concentrated to dryness under reducedpressure and subjected to column chromatography on silica gel(CHCl₃-Acetone, 9:1) to giveN2,N4-bis[3-(tert-butoxycarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6+CD₃OD): δ 7.96 (d, 1H, J=4.1 Hz), 7.83 (m, 1H), 7.60 (m,1H), 7.34-7.42 (m, 2H), 7.15-7.19 (m, 2H), 7.06 (t, 1H, J=8.2 Hz), 6.93(d, 1H, J=8.2 Hz), 1.43 (s, 9H), 1.40 (s, 9H); LCMS: purity: 93.2%; MS(m/e): 511.06 (M⁺, 100).

7.3.157N2,N4-Bis[4-(tert-butoxycarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R950120)

2,4-Dichloro-5-fluoropyrimidine (75 mg, 0.45 mmol) was dissolved in amixture of MeOH (2 ml) and H₂O (0.2 ml).4-tert-butoxycarbonylaminoaniline (374 mg, 1.8 mmol) was added and themixture was refluxed for 24 hours (70° C. oil-bath temperature). Themixture was cooled to 22° C., concentrated to dryness under reducedpressure and subjected to column chromatography on silica gel(CHCl₃-Acetone, 9:1) to giveN2,N4-bis[4-(tert-butoxycarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6+CD₃OD): δ 7.96 (d, 1H, J=3.5 Hz), 7.63 (d, 2H, J=8.8Hz), 7.49 (d, 2H, J=8.8 Hz), 7.37 (d, 2H, J=8.8 Hz), 7.24 (d, 2H, J=8.8Hz), 1.45 (s, 9H), 1.43 (s, 9H); LCMS: purity: 97.9%; MS (m/e): 511.04(M⁺, 100).

7.3.158N2,N4-Bis[2-[2-(methylamino)ethyleneaminocarbonyl]-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine(R950170)

N2,N4-Bis[2-(ethoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine(10 mg, 0.02 mmol) was dissolved in EtOH. To this was addedN-methyl-1,2-aminoethane (0.1 ml: 0.1 ml) and the mixture was refluxedfor 3 days (70° C. oil-bath temperature). The mixture was cooled to 22°C., diluted with water and filtered. The residue was subjected to columnchromatography on silica gel (CHCl₃-Acetone, 2:1) to giveN2,N4-bis[2-[2-(methylamino)ethyleneaminocarbonyl]-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6+CD₃OD): δ 8.14 (s, 1H), 8.02 (s, 1H), 7.99 (d, 1H, J=2.4Hz), 7.35-7.68 (m, 5H), 7.17 (s, 1H), 3.41 (m, 2H), 2.75 (m, 2H), 2.35(s, 3H); LCMS: purity: 84.2%; MS (m/e): 561.08 (M⁺, 100).

7.3.159N2,N4-Bis[2-(2-hydroxyethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine(R950167)

In like manner to the preparation ofN2,N4-bis[2-[2-(methylamino)ethyleneaminocarbonyl]-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis[2-(ethoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamineand 2-aminoethanol were reacted to prepareN2,N4-bis[2-(2-hydroxyethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 14.22 min.; purity: 95.7%; MS (m/e): 535.01 (MH⁺).

7.3.160N2,N4-Bis[2-(2-aminoethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine(R950168)

In like manner to the preparation ofN2,N4-bis[2-[2-(methylamino)ethyleneaminocarbonyl]-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis[2-(ethoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamineand 1,2-diaminoethane were reacted to prepareN2,N4-bis[2-(2-aminoethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 13.15 min.; purity: 95.8%; MS (m/e): 532.99 (MH⁺).

7.3.161N2,N4-Bis[2-(2-(N-benzylamino)ethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine(R950169)

In like manner to the preparation ofN2,N4-bis[2-[2-(methylamino)ethyleneaminocarbonyl]-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis[2-(ethoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamineand N-benzyl-1,2-diaminoethane were reacted to prepareN2,N4-bis[2-(2-(N-benzylamino)ethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine. LCMS: ret.time: 13.15 min.; purity: 95.8%; MS (m/e): 713.10 (MH⁺).

7.3.162N2,N4-Bis[2-(N-morpholinocarbonyl)benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine(R950172)

In like manner to the preparation ofN2,N4-bis[2-[2-(methylamino)ethyleneaminocarbonyl]-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis[2-(ethoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamineand morpholine were reacted toN2,N4-bis[2-(N-morpholinocarbonyl)benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6+CD₃OD): δ 8.13 (d, 1H, J=2.7 Hz), 8.06 (d, 1H, J=2.4Hz), 8.03 (d, 1H, J=3.6 Hz), 7.63 (dd, 1H, J=2.4, 8.8 Hz), 7.57 (d, 1H,J=9.3 Hz), 7.49 (dd, 1H, J=2.4, 8.4 Hz), 7.42 (d, 1H, J=8.8 Hz), 7.25(s, 1H), 7.05 (s, 1H), 4.09 (m, 4H), 3.65 (m, 4H); LCMS: ret. time:18.04 min.; purity: 83.2%; MS (m/e): 587.04 (MH⁺).

7.3.163N2,N4-Bis[2-(2-N-morpholinoethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine(R950173)

In like manner to the preparation ofN2,N4-bis[2-[2-(methylamino)ethyleneaminocarbonyl]-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis[2-(ethoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamineand N-(2-aminoethyleneamino)morpholine were reacted to prepareN2,N4-bis[2-(2-N-morpholinoethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6+CD₃OD): δ 8.16 (d, 1H, J=2.4 Hz), 8.03-8.05 (m, 2H),7.71 (dd, 1H, J=1.8, 8.8 Hz), 7.56 (d, 1H, J=8.8 Hz), 7.42 (d, 1H, J=8.8Hz), 7.36 (s, 1H), 7.19 (s, 1H), 4.19 (m, 4H), 3.38 (m, 4H), 3.16 (t,2H, J=6.3 Hz), 2.28 (t, 2H, J=6.3 Hz); LCMS: ret. time: 12.85 min.;purity: 93.8%; MS (m/e): 673.35 (MH⁺).

7.3.164 N2,N4-Bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine(R950135)

2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) was dissolved in amixture of MeOH (1 ml) and H₂O (0.1 ml). 3-amino-4-nitroaniline (184 mg,1.2 mmol) was added and the mixture was refluxed for 3 days (70° C.oil-bath temperature). The mixture was cooled to 22° C., concentrated todryness under reduced pressure and subjected to column chromatography onsilica gel (CHCl₃-Acetone, 2:1) to giveN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(DMSO-d6+CD₃OD): δ 8.21 (d, 1H, J=2.9 Hz), 7.89 (m, 3H), 7.56 (d, 1H,J=2.3 Hz), 7.01 (m, 1H), 6.81 (dd, 1H, J=2.3, 9.4 Hz); LCMS: purity:91.1%; MS (m/e): 401.00 (M⁺, 100).

7.3.165N2,N4-Bis(3-amino-2,4-difluorophenyl)-5-fluoro-2,4-pyrimidinediamine(R950138)

In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-amino-2,4-difluoroaniline werereacted to prepareN2,N4-bis(3-amino-2,4-difluorophenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 16.98 min.; purity: 91.7%; MS (m/e): 382.97 (MH⁺).

7.3.166 N2,N4-Bis(3-amino-4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950139)

In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-amino-4-ethoxyaniline were reactedto prepareN2,N4-bis(3-amino-4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 14.29 min.; purity: 93.4%; MS (m/e): 399.09 (MH⁺).

7.3.167N2,N4-Bis(3-amino-5-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R950134)

In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-amino-5-methoxycarbonylanilinewere reacted to prepareN2,N4-bis(3-amino-5-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 14.72 min.; purity: 93.8%; MS (m/e): 427.02 (MH⁺).

7.3.168N2,N4-Bis(3-amino-5-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine(R950140)

In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-amino-5-trifluoromethylanilinewere reacted to prepareN2,N4-bis(3-amino-5-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 23.35 min.; purity: 100%; MS (m/e): 446.92 (MH⁺).

7.3.169 N2,N4-Bis(3-amino-5-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine(R950141)

In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-amino-5-chloroaniline were reactedto prepareN2,N4-bis(3-amino-5-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 19.25 min.; purity: 99.3%; MS (m/e): 378.91 (MH⁺).

7.3.170N2,N4-Bis(4-hydroxy-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine(R950093)

In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-hydroxy-3-trifluoromethylanilinewere reacted to prepareN2,N4-bis(4-hydroxy-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 22.06 min.; purity: 99.1%; MS (m/e): 448.88 (MH⁺).

7.3.171 N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine HydrogenChloride salt (R950107)

N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine was treated with2 equivalents of HCl in dioxane. The volatiles were removed underreduced pressure to giveN2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine hydrogenchloride salt. LCMS: ret. time: 9.74 min.; purity: 91.3%; MS (m/e):311.06 (MH⁺).

7.3.172 N2,N4-Bis(4-aminophenyl)-5-fluoro-2,4-pyrimidinediamine HydrogenChloride Salt (R950121)

N2,N4-Bis(4-aminophenyl)-5-fluoro-2,4-pyrimidinediamine was treated with2 equivalents of HCl in dioxane. The volatiles were removed underreduced pressure to giveN2,N4-bis(4-aminophenyl)-5-fluoro-2,4-pyrimidinediamine HydrogenChloride Salt. LCMS: ret. time: 11.15 min.; purity: 100%; MS (m/e):311.09 (MH⁺).

7.3.173 N2,N4-Bis(3-aminophenyl)-2,4-pyrimidinediamine (R950109)

In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 3-aminoaniline were reacted to prepareN2,N4-bis(3-aminophenyl)-2,4-pyrimidinediamine. LCMS: ret. time: 8.90min.; purity: 91%; MS (m/e): 293.06 (MH⁺).

7.3.174 N2,N4-Bis(3-amino-2,4-difluorophenyl)-2,4-pyrimidinediamine(R950131)

In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 3-amino-2,4-difluoroaniline were reacted toprepare N2,N4-bis(3-amino-2,4-difluorophenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 16.62 min.; purity: 96.7%; MS (m/e): 364.99 (MH⁺).

7.3.175 N2,N4-Bis(3-amino-4-ethoxyphenyl)-2,4-pyrimidinediamine(R950142)

In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 3-amino-4-ethoxyaniline were reacted toprepare N2,N4-bis(3-amino-4-ethoxyphenyl)-2,4-pyrimidinediamine. LCMS:ret. time: 14.38 min.; purity: 99.7%; MS (m/e): 381.07 (MH⁺).

7.3.176 N2,N4-Bis(3-amino-5-methoxycarbonylphenyl)-2,4-pyrimidinediamine(R950132)

In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 3-amino-5-methoxycarbonylaniline were reactedto prepareN2,N4-bis(3-amino-5-methoxycarbonylphenyl)-2,4-pyrimidinediamine. LCMS:ret. time: 15.25 min.; purity: 93.6%; MS (m/e): 409.02 (MH⁺).

7.3.177 N2,N4-Bis(3-amino-5-trifluoromethylphenyl)-2,4-pyrimidinediamine(R950143)

In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 3-amino-5-trifluoromethylaniline were reactedto prepareN2,N4-bis(3-amino-5-trifluoromethylphenyl)-2,4-pyrimidinediamine. LCMS:ret. time: 23.23 min.; purity: 99.1%; MS (m/e): 428.95 (MH⁺).

7.3.178 N2,N4-Bis(3-amino-5-chlorophenyl)-2,4-pyrimidinediamine(R950133)

In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 3-amino-5-chloroaniline were reacted toprepare N2,N4-bis(3-amino-5-chlorophenyl)-2,4-pyrimidinediamine. LCMS:ret. time: 19.45 min.; purity: 100%; MS (m/e): 360.93 (MH⁺).

7.3.179N2,N4-Bis[3-amino-4-(N-phenylamino)-phenyl]-5-fluoro-2,4-pyrimidinediamine(R950125)

In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-amino-4-(N-phenylamino)-anilinewere reacted to prepareN2,N4-bis[3-amino-4-(N-phenylamino)-phenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 23.67 min.; purity: 100%; MS (m/e): 476.36 (MH⁺).

7.3.180N2,N4-Bis[3-amino-4-(N-phenylamino)-phenyl]-2,4-pyrimidinediamine(R950123)

In like manner the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 3-amino-4-(N-phenylamino)-aniline werereacted to prepareN2,N4-bis[3-amino-4-(N-phenylamino)-phenyl]-2,4-pyrimidinediamine. LCMS:ret. time: 23.77 min.; purity: 77.8%; MS (m/e): 475.04 (MH⁺).

7.3.181 N2,N4-Bis(5-amino-2-methylphenyl)-5-fluoro-2,4-pyrimidinediamine(R950157)

In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 5-amino-2-methylaniline were reactedto prepareN2,N4-bis(5-amino-2-methylphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 10.61 min.; purity: 83.4%; MS (m/e): 339.13 (MH⁺).

7.3.182 N2,N4-Bis(5-amino-2-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine(R950158)

In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 5-amino-2-fluoroaniline were reactedto prepareN2,N4-bis(5-amino-2-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 11.48 min.; purity: 95.6%; MS (m/e): 347.04 (MH⁺).

7.3.183 N2,N4-Bis(3-amino-4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine(R950159)

In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-amino-4-fluoroaniline were reactedto prepareN2,N4-bis(3-amino-4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 18.74 min.; purity: 95.6%; MS (m/e): 347.29 (MH⁺).

7.3.184 N2,N4-Bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine(R950146)

2,4-Dichloro-5-fluoropyrimidine (33 mg, 0.2 mmol) was dissolved in amixture of MeOH (1 ml) and H₂O (0.1 ml). 2-Methyl-5-nitroaniline (122mg, 0.8 mmol) was added and the mixture was refluxed for 2 days (70° C.oil-bath temperature). The mixture was cooled to 22° C., concentrated todryness under reduced pressure and subjected to column chromatography onsilica gel (CHCl₃-Acetone, 9:1) to giveN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(DMSO-d6+CD₃OD): δ 8.31 (d, 1H, J=2.3 Hz), 8.20 (d, 1H, J=2.3 Hz), 8.06(d, 1H, J=3.5 Hz), 7.91 (dd, 1H, J=2.3, 8.2 Hz), 7.65 (dd, 1H, J=2.9,8.8 Hz), 7.41 (m, 1H), 7.28 (d, 1H, J=8.2 Hz), 2.28 (s, 3H), 2.24 (s,3H); LCMS purity: 87.4%; MS (m/e): 399.20 (M⁺, 100).

7.3.185 N2,N4-Bis(2-fluoro-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine(R950147)

In like manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-fluoro-5-nitroaniline were reactedto prepareN2,N4-bis(2-fluoro-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 31.07 min.; purity: 93.6%; MS (m/e): 407.14 (MH⁺).

7.3.186 N2,N4-Bis(4-fluoro-3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine(R950148)

In like manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-fluoro-3-nitroaniline were reactedto prepareN2,N4-bis(4-fluoro-3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 27.17 min.; purity: 94.3%; MS (m/e): 406.96 (MH⁻).

7.3.187 N2,N4-Bis(4-methyl-3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine(R950144)

In like manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-methyl-3-nitroaniline were reactedto prepareN2,N4-bis(4-methyl-3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 27.40 min.; purity: 96.6%; MS (m/e): 399.00 (MH⁺).

7.3.188 N2,N4-Bis(4-chloro-3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine(R950149)

In like manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-chloro-3-nitroaniline were reactedto prepareN2,N4-bis(4-chloro-3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 35.63 min.; purity: 98.9%; MS (m/e): 439.09 (MH⁺).

7.3.189N2,N4-Bis(2-hydroxyethyleneamino-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine(R950150)

In like manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and2-hydroxyethyleneamino-5-nitroaniline were reacted to prepareN2,N4-bis(2-hydroxyethyleneamino-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 17.90 min.; purity: 97.8%; MS (m/e): 489.19 (MH⁺).

7.3.190N2,N4-Bis(2-methoxy-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine(R950151)

In like manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-methoxy-5-nitroaniline werereacted to prepareN2,N4-bis(2-methoxy-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 31.46 min.; purity: 95.9%; MS (m/e): 431.22 (MH⁺).

7.3.191 N2,N4-Bis(4-fluoro-3-nitrophenyl)-2,4-pyrimidinediamine(R950152)

In like manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 4-fluoro-3-nitroaniline were reacted toprepare N2,N4-bis(4-fluoro-3-nitrophenyl)-2,4-pyrimidinediamine. LCMS:ret. time: 30.92 min.; purity: 94.4%; MS (m/e): 389.31 (MH⁺).

7.3.192 N2,N4-Bis(4-methyl-3-nitrophenyl)-2,4-pyrimidinediamine(R950153)

In like manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 4-methyl-3-nitroaniline were reacted toprepare N2,N4-bis(4-methyl-3-nitrophenyl)-2,4-pyrimidinediamine. LCMS:ret. time: 31.22 min.; purity: 99.6%; MS (m/e): 381.35 (MH⁺).

7.3.193 N2,N4-Bis(4-chloro-3-nitrophenyl)-2,4-pyrimidinediamine(R950154)

In like manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 4-chloro-3-nitroaniline were reacted toprepare N2,N4-bis(4-chloro-3-nitrophenyl)-2,4-pyrimidinediamine. LCMS:ret. time: 37.24 min.; purity: 99.1%; MS (m/e): 421.30 (MH⁺).

7.3.194 N2,N4-Bis(2-hydroxy-5-nitrophenyl)-2,4-pyrimidinediamine(R950155)

In like manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 2-hydroxy-5-nitroaniline were reacted toprepare N2,N4-bis(2-hydroxy-5-nitrophenyl)-2,4-pyrimidinediamine. LCMS:ret. time: 23.26 min.; purity: 100%; MS (m/e): 385.33 (MH⁺).

7.3.195N2,N4-Bis(2-hydroxyethyleneamino-5-nitrophenyl)-2,4-pyrimidinediamine(R950156)

In like manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 2-hydroxyethyleneamino-5-nitroaniline werereacted to prepareN2,N4-bis(2-hydroxyethyleneamino-5-nitrophenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 17.87 min.; purity: 97.2%; MS (m/e): 470.99 (MH⁺).

7.3.196N2,N4-Bis[3-(N-isopropyl)aminophenyl]-5-fluoro-2,4-pyrimidinediamine(R950166)

N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine, acetone andsodiumcyanoborohydride were reacted together to giveN2,N4-bis[3-(N-isopropyl)aminophenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 14.07 min.; purity: 90.3%; MS (m/e): 395.14 (MH⁺).

7.3.197N2,N4-Bis[3-N-(2-hydroxy-1-methylethyl)aminophenyl]-5-fluoro-2,4-pyrimidinediamine(R950171)

N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,1-hydroxyacetone and sodiumcyanoborohydride were reacted to giveN2,N4-bis[3-N-(2-hydroxy-1-methylethyl)aminophenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 11.97 min.; purity: 79.01%; MS (m/e): 427.12 (MH⁺).

7.3.198N2,N4-Bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine(R950177)

N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and tert-butylbromoacetate were reacted together to giveN2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 29.34 min.; purity: 97.2%; MS (m/e): 427.07 (MH⁺).

7.3.199N4-(3-Aminophenyl)-N2-(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine(R950178)

In like manner to the preparation ofN2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and tert-butylbromoacetate were reacted together to giveN4-(3-aminophenyl)-N2-(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 18.33 min.; purity: 94.5%; MS (m/e): 369.09 (MH⁺).

7.3.200N2-(3-Aminophenyl)-N4-(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine(R950179)

In like manner to the preparation ofN2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and tert-butylbromoacetate were reacted together to giveN2-(3-aminophenyl)-N4-(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 18.82 min.; purity: 85.8%; MS (m/e): 369.11 (MH⁺).

7.3.201N2,N4-Bis(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine(R950184)

In like manner to the preparation ofN2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and ethylbromoacetate were reacted together to giveN2,N4-bis(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 23.41 min.; purity: 96.3%; MS (m/e): 483.08 (MH⁺).

7.3.202N2,N4-Bis(3-ethoxycarbonylmethyleneaminophenyl)-N2-(ethoxycarbonylmethyl)-5-fluoro-2,4-pyrimidinediamine(R950183)

In like manner to the preparation ofN2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and ethylbromoacetate were reacted together to giveN2,N4-bis(3-ethoxycarbonylmethyleneaminophenyl)-N2-(ethoxycarbonylmethyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 25.65 min.; purity: 92.5%; MS (m/e): 569.08 (MH⁺).

7.3.203N2-(3-Aminophenyl)-N4-(3-hydroxyethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamineandN4-(3-Aminophenyl)-N2-(3-hydroxyethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine(R950180)

In like manner to the preparation ofN2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and1-bromo-2-hydroxyethane were reacted together to give a unseparablemixture ofN2-(3-aminophenyl)-N4-(3-hydroxyethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamineandN4-(3-aminophenyl)-N2-(3-hydroxyethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 9.84 min.; purity: 89.5%; MS (m/e): 355.10 (MH⁺).

7.3.204N2,N4-Bis(3-hydroxyethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine(R950181)

In like manner to the preparation ofN2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and1-bromo-2-hydroxyethane were reacted together to giveN2,N4-bis(3-hydroxyethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 11.46 min.; purity: 83.3%; MS (m/e): 399.12 (MH⁺).

7.3.205N2,N4-Bis[3-(N-benzyloxyethyleneamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R950174)

In like manner to the preparation ofN2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and1-benzyloxy-2-bromoethane were reacted together to giveN2,N4-bis[3-(N-benzyloxyethyleneamino)phenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 32.92 min.; MS (m/e): 579.17 (MH⁺).

7.3.206N2-(3-Aminophenyl)-N4-[3-(N-benzyloxyethyleneamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R950175)

In like manner to the preparation ofN2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and1-benzyloxy-2-bromoethane were reacted together to giveN2-(3-aminophenyl)-N4-[3-(N-benzyloxyethyleneamino)phenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 23.79 min.; MS (m/e): 445.11 (MH⁺).

7.3.207N4-(3-Aminophenyl)-N2-[3-(N-benzyloxyethyleneamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R950176)

In like manner to the preparation ofN2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and1-benzyloxy-2-bromoethane were reacted together to giveN4-(3-aminophenyl)-N2-[3-(N-benzyloxyethyleneamino)phenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 23.64 min.; MS (m/e): 445.13 (MH⁺).

7.3.208N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926210)

To a solution of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (0.028g, 0.1 mmol) in MeOH: H₂O (1.8: 0.2 mL) was added 3-hydroxyaniline(0.033 g, 0.3 mmol) and heated in a sealed tube at 100° C. for 24 h. Theresulting reaction was diluted with H₂O (10 mL), acidified with 2N HCl(pH>2), saturated and the resulting solid was filtered to give thedesired product,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl))-2,4-pyrimidinediamine(R926210). Purification can be done by filtration through a pad ofsilica gel using 1-5% MeOH in CH₂Cl₂ or by crystallization using anappropriate solvent system. ¹H NMR (CDCl₃+CD₃OD): δ 7.76 (bs, 1H), 7.30(d, 1H, J=2.4 Hz), 7.10 (m, 1H), 7.03 (t, 1H, J=8.1 Hz), 6.89 (dd, 2H,J=2.4 and 9 Hz), 6.78 (d, 1H, J=8.7 Hz), 6.42 (dd, 1H, J=2.4 and 9 Hz),4.22 (m, 4H); ¹⁹F NMR (CDCl₃+CD₃OD): −47196; LCMS: ret. time: 19.55min.; purity: 95%; MS (m/e): 355 (MH⁺).

Note: When the substrate has ethyl, butyl, benzyl etc. ester functionsand the reaction is carried out in methanol as a solvent, the crossesterification to produce methyl ester was observed.

7.3.209N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[3-(hydroxymethyl)phenyl]-2,4-pyrimidinediamine(R925758)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[3-(hydroxymethyl)phenyl]-4-pyrimidineamine and3,4-ethylenedioxyaniline were reacted to yieldN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[3-(hydroxymethyl)phenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.92 (d, 1H, J=3.0 Hz), 7.78 (bs, 1H), 7.41-7.31 (m,3H), 7.12 (d, 1H, J=7.2 Hz), 6.94 (bs, 1H), 6.81-6.75 (m, 3H), 4.68 (s,2H), 4.25 (s, 4H); ¹⁹F NMR (CDCl₃): −47438; LCMS: ret. time: 17.73 min.;purity: 100%; MS (m/e): 369 (MH⁺).

7.3.210N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(hydroxymethyl)phenyl]-2,4-pyrimidinediamine(R925760)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-(hydroxymethyl)phenyl]-4-pyrimidineamine and3,4-ethylenedioxyaniline were reacted to yieldN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[4-(hydroxymethyl)phenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.92 (bs, 1H), 7.62 (d, 2H, J=8.7 Hz), 7.36 (d, 2H,J=8.7 Hz), 7.19 (d, 1H, J=2.1), 6.87 (dd, 1H, J=2.7 and 8.7 Hz), 6.79(d, 1H, J=8.7 Hz), 4.68 (s, 2H), 4.28-4.23 (m, 4H); ¹⁹F NMR (CDCl₃):−4.7466; LCMS: ret. time: 17.86 min.; purity: 93%; MS (m/e): 369 (MH⁺).

7.3.211N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-hydroxy-2-phenylethyl)-2,4-pyrimidinediamine(R925765)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(2-hydroxy-2-phenylethyl)-4-pyrimidineamine and3,4-ethylenedioxyaniline were reacted to yieldN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-hydroxy-2-phenylethyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.79 (s, 1H), 7.48 (m, 5H), 6.89-6.71 (m, 3H),5.41-5.38, 4.97 (dd, 1H, J=3.6 and 7.5 Hz), 4.28-4.22 (m, 4H), 3.88(ddd, 1H, J=4.2, 7.2, and 14.1), 3.64-3.55 (m, 1H); ¹⁹F NMR (CDCl₃):−47910; LCMS: ret. time: 20.47 min.; purity: 88%; MS (m/e): 383 (MH⁺).

7.3.212 N2-(3,4-Ethylendioxyphenyl)-5-fluoro-N4-[(2R)-hydroxy-(1S)-methyl-2-phenylethyl)-2,4-pyrimidinediamine (R925766)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[(2R)-hydroxy-(1S)-methyl-2-phenylethyl)-4-pyrimidineamineand 3,4-ethylenedioxyaniline were reacted to yieldN2-(3,4-ethylendioxyphenyl)-5-fluoro-N4-[(2R)-hydroxy-(1S)-methyl-2-phenylethyl)-2,4-pyrimidinediamine. ¹H NMR (CDCl₃): δ 7.80(bs, 1H), 7.71 (bs, 1H), 7.36-7.23 (m, 6H), 6.91 (dd, 1H, J=3.0 and 9.0Hz), 6.80 (d, 1H, J=9.0 Hz), 5.17 (d, 1H, J=8.1 Hz), 5.01 (d, 1H, J=3.0Hz), 4.56-4.50 (m, 1H), 4.24 (s, 4H), 1.10 (d, 3H, J=6.3 Hz); ¹⁹F NMR(CDCl₃): −47840; LCMS: ret. time: 21.43 min.; purity: 99%; MS (m/e): 397(MH⁺).

7.3.213N4-Cyclohexyl-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R925794)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-cyclohexyl-5-fluoro-4-pyrimidineamine and3,4-ethylenedioxyaniline were reacted to yieldN4-cyclohexyl-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.62 (d, 1H, J=4.2 Hz), 7.31 (d, 1H, J=2.1 Hz), 6.86(dd, 1H, J=2.4 and 8.7 Hz), 6.68 (d, 1H, J=8.7 Hz), 4.23-4.16 (m, 4H),3.99-3.89 (m, 1H), 2.03 (dd, 2H, J=2.1 and 12.3 Hz), 1.80 (dt, 2H, J=3.0and 13.5 Hz), 1.72-1.65 (m, 1H), 1.49-1.20 (m, 5H); ¹⁹F NMR (CD₃OD):−48332; LCMS: ret. time: 24.54 min.; purity: 95%; MS (m/e): 345 (MH⁺).

7.3.214N4-(4-Carboxycyclohexyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R925795)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-(4-carboxycyclohexyl)-2-chloro-5-fluoro-4-pyrimidineamine and3,4-ethylenedioxyaniline were reacted to yieldN4-(4-carboxycyclohexyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.62 (d, 1H, J=4.2 Hz), 7.31 (d, 1H, J=2.4 Hz), 6.84(dd, 1H, J=2.4 and 8.7 Hz), 6.70 (d, 1H, J=8.7 Hz), 4.23-4.18 (m, 4H),3.99-4.08 (m, 1H), 2.59 (t, 1H, J=3.9 Hz), 2.16-2.09 (m, 2H), 1.91-1.84(m, 2H), 1.78-1.57 (m, 4H); ¹⁹F NMR (CD₃OD): −48152; LCMS: ret. time:19.31 min.; purity: 96%; MS (m/e): 389 (MH⁺).

7.3.215N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R925796)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3,4-ethylenedioxyaniline were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.30 (s, 1H), 9.12 (bs, 1H), 8.91 (bs, 1H), 8.02 (d,1H, J=3.3 Hz), 7.35-7.30 (m, 1H), 7.24-7.21 (m, 1H), 7.12 (t, 1H, J=1.8Hz), 7.09-7.04 (m, 2H), 6.67 (d, 1H, J=9.0), 6.46 (dd, 1H, J=1.8 and 8.4Hz), 4.18-4.12 (m, 4H); ¹⁹F NMR (DMSO-d6): −46594; LCMS: ret. time:18.43 min.; purity: 97%; MS (m/e): 355 (MH⁺).

7.3.216N2-Allyl-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R925823)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine andallylamine were reacted to yieldN2-allyl-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CD₃OD): δ 7.71 (bs, 1H), 7.37 (d, 1H, J=2.4 Hz), 7.07 (dd, 1H,J=2.4 and 8.7 Hz), 6.75 (d, 1H, J=8.7 Hz), 5.98-5.85 (m, 1H), 5.19 (dq,1H, J=1.8 and 16.8 Hz), 5.06 (dq, 1H, J=1.8 and 10.5 Hz), 4.24-4.18 (m,4H), 3.92-3.68 (m, 2H); ¹⁹F NMR (CD₃OD): −48552; LCMS: ret. time: 19.36min.; purity: 95%; MS (m/e): 303 (MH⁺).

7.3.217N4-(3,4-Ethylenedioxyphenyl)-N2-(4-ethylphenyl)-5-fluoro-2,4-pyrimidinediamine(R926237)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-ethylaniline were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-N2-(4-ethylphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.87 (bs, 1H), 7.42 (d, 2H, J=8.7 Hz), 7.26 (d, 1H,J=3.0 Hz), 7.13-7.08 (m, 3H), 6.95 (dd, 1H, J=2.4 and 8.7 Hz), 6.82 (d,1H, J=9.0 Hz), 6.60 (bs, 1H), 4.23 (s, 4H), 2.59 (q, 2H, J=7.5 Hz), 1.20(t, 3H, J=7.5 Hz); ¹⁹F NMR (CDCl₃): −47549; LCMS: ret. time: 25.31 min.;purity: 99%; MS (m/e): 367 (MH⁺).

7.3.218N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine(R926690)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and2-methoxycarbonyl-5-aminobenzofuran were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.68 (bs, 1H), 8.13-8.10 (m, 2H), 7.63-7.54 (m, 3H),7.27 (bs, 1H), 7.10 (d, 1H, J=8.7 Hz), 6.80 (d, 1H, J=8.1 Hz), 4.21 (s,4H), 3.88 (s, 3H); LCMS: ret. time: 23.22 min.; purity: 95%; MS (m/e):437 (MH⁺).

7.3.2195-Fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine(R926704)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-(isopropoxy)phenyl]-4-pyrimidineamine and2-methoxycarbonyl-5-aminobenzofuran were reacted to yield5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.04 (d, 1H, J=1.8 Hz), 7.49-7.41 (m, 4H), 7.35 (dd,1H, J=2.4 and 8.7 Hz), 7.14 (bs, 1H), 6.90 (d, 2H, J=9.3 Hz), 6.70 (bs,1H), 4.56 (2q, 1H, J=5.7 Hz), 3.98 (s, 3H), 1.37 (d, 6H, J=5.7 Hz);LCMS: ret. time: 25.52 min.; purity: 98%; MS (m/e): 437 (MH⁺).

7.3.2205-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(2-hydroxyethyl)oxyphenyl]-2,4-pyrimidinediamine(R926376)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)]-4-pyrimidineamine and4-(2-hydroxyethyloxy)aniline were reacted to yield5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(2-hydroxyethyl)oxyphenyl]-2,4-pyrimidinediamine.¹H NMR (D₂O): δ 8.40 (d, 1H J=4 Hz), 7.57 (m, 6H), 7.12 (m, 2H), 6.90(m, 2H), 4.40 (m, 4H) 2.2 (s, 3H); LCMS: ret. time: 13.61 min.; purity:97%; MS (m/e): 357 (MH⁺).

7.3.221N2-[4-(2-N,N-Dimethylamino)ethoxyphenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R909236)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)]-4-pyrimidineamine and4-(2-N,N-dimethylamino)ethoxyaniline were reacted to yieldN2-[4-(2-N,N-dimethylamino)ethoxyphenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.80 (d, 1H J=4 Hz), 7.47 (dd, 1H, J=6.8 Hz, 2.7 Hz),7.44 (m, 1H), 7.05 (m, 1H), 6.85 (m, 1H), 6.78 (m, 2H), 4.16 (m, 2H),3.03 (m, 2H), 2.55 (s, 6H); LCMS: ret. time: 12.74 min.; purity: 98%; MS(m/e): 384 (MH⁺).

7.3.222N2-(1,4-Benzoxazin-3-on-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R909238)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)]-4-pyrimidineamine and6-amino-1,4-benzoxazin-3-one were reacted to yieldN2-(1,4-benzoxazin-3-on-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 8.18 (d, 1H J=4 Hz), 7.17 (m, 3H), 7.09 (m, 1H),7.06 (m, 1H), 6.58 (m, 1H) 4.52 (s, 3H); LCMS: ret. time: 17.18 min.;purity: 99%; MS (m/e): 368 (MH⁺).

7.3.223N2-(1,4-Benzoxazin-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R909241)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)]pyrimidineamine and6-amino-1,4-benzoxazine were reacted to yieldN2-(1,4-benzoxazin-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.82 (d, 1H, J=4 Hz), 7.15 (m, 3H), 6.68 (m, 2H), 6.52(m, 2H), 6.52 (m, 1H), 4.18 (m, 2H), 3.37 (m, 2H); LCMS: ret. time 17.42min.; purity: 95%; MS (m/e): 354 (MH⁺).

7.3.224N4-(1,4-Benzoxazin-6-yl)-N2-[3-ethoxyocarbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R909242)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)-N2-chloro-5-fluoro-4-pyrimidineamine and3-ethoxyocarbonylmethyleneoxyaniline were reacted to yieldN4-(1,4-benzoxazin-6-yl)-N2-(3-ethoxyocarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ □□□□ (d, 1H, J=4 Hz), 7.15 (m, 4H), 6.84 (m, 2H), 6.62(m, 1H), 4.65 (s, 2H), 4.15 (m, 4H), 3.28 (m, 2H), 1.19 (t, 3H. J=7 Hz);LCMS: ret. time 22.6 min.; purity: 94%; MS (m/e): 439 (MH⁺).

7.3.225N2-(1,4-Benzoxazin-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R909243)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)-N2-chloro-5-fluoro-4-pyrimidineamine and3-aminophenol were reacted to yieldN4-(1,4-benzoxazin-6-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 7.83 (d, 1H, J=4 Hz), 7.18 (m, 3H), 6.68 (m, 2H),6.45 (m, 2H), 6.52 (m, 1H), 4.22 (m, 2H), 3.31 (m, 2H); LCMS: ret. time:17.24; purity: 96%; MS (m/e): 354 (MH⁺).

7.3.226N4-(1,4-Benzoxazin-6-yl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R909245)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)-N2-chloro-5-fluoro-4-pyrimidineamine and3,5-dimethoxyaniline were reacted to yieldN4-(1,4-benzoxazin-6-yl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 8.12 (d, 1H, J=4 Hz), 6.80 (m, 4H), 6.60 (m, 1H),6.05 (m, 1H), 4.02 (m, 2H), 3.65 (s, 6H), 3.31 (m, 2H); LCMS: ret. time:22.38 min.; purity: 99%; MS (m/e): 398 (MH⁺).

7.3.227N4-(1,4-Benzoxazin-6-yl)-N2-(3-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine(R909246)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)-N2-chloro-5-fluoro-4-pyrimidineamine and3-tert-butylaniline were reacted to yieldN4-(1,4-benzoxazin-6-yl)-N2-(3-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 8.03 (d, 1H, J=4 Hz), 7.5 (m, 1H), 7.4 (m, 1H), 7.18(m, 1H), 7.02 (m, 1H), 6.80 (m, 2H), 6.60 (m, 1H), 4.02 (m, 2H), 3.31(m, 2H), 1.2 (s, 9H); LCMS: ret. time: 26.64 min.; purity: 99%; MS(m/e): 508 (MH⁺).

7.3.228N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[4-(2-hydroxyethyl)oxyphenyl]-2,4-pyrimidinediamine(R909248)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)-N2-chloro-5-fluoro-4-pyrimidineamine and4-(2-hydroxyethyl)oxyaniline were reacted to yieldN4-(1,4-benzoxazin-6-yl)-5-fluoro-N2-[4-(2-hydroxyethyl)oxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 7.98 (d, 1H, J=4 Hz), 7.52 (m, 1H), 7.4 (m, 3H),6.90 (m, 2H), 6.68 (m, 1H), 4.56 (s, 2H), 4.02 (m, 2H), 3.75 (m, 2H),3.31 (m, 4H); LCMS: ret. time: 26.67 min.; purity: 93%; MS (m/e): 399(MH⁺).

7.3.229N2-(2,3-Dihydrobenzofuran-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R909250)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)]-4-pyrimidineamine and5-amino-2,3-dihydrobenzofuran were reacted to yieldN2-(2,3-dihydrobenzofuran-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹HNMR (DMSO-d6): δ 8.09 (d, 1H), 8.00 (m, 1H), 7.82 (m, 1H), 7.57 (m,1H), 7.22 (m, 1H), 7.08 (m, 1H), 6.99 (m, 1H), 6.82 (m, 1H), 6.70 (m,1H), 6.42 (m, 1H), 4.49 (m, 2H), 3.15 (m, 2H); LCMS: ret time: 19.39min.; MS (m/e): 338 (MH⁺).

7.3.230N4-(1,4-Benzoxazin-6-yl)-N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine(R909255)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)-N2-chloro-5-fluoro-4-pyrimidineamine and3-chloro-4-hydroxy-5-methylaniline were reacted to yieldN4-(1,4-benzoxazin-6-yl)-N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 7.89 (d, 1H, J=4 Hz), 7.25 (m, 1H), 7.14 (m, 1H),6.80 (m, 2H), 6.82 (m, 1H), 4.29 (s, 2H), 3.35 (m, 2H), 2.20 (s, 3H);LCMS: ret. time: 17.05 min.; purity: 99%; MS (m/e): 402 (MH⁺).

7.3.2315-Fluoro-N2-(2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine(R926706)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine and5-amino-2,3-dihydro-2-(methoxycarbonyl)benzofuran were reacted to yield5-fluoro-N2-(2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.87 (d, 1H, J=3.0 Hz), 7.47-7.42 (m, 3H), 7.12 (dd,1H, J=2.4 and 8.4 Hz), 6.87 (d, 2H, J=9.6 Hz), 6.80 (d, 1H, J=8.7 Hz),6.63 (d, 1H, J=2.4 Hz), 5.21 (dd, 1H, J=6.3 and 10.5 Hz), 4.53 (2q, 1H,J=5.7 Hz), 3.80 (s, 3H), 3.52 (dd, 1H, J=10.5 and 15.9 Hz), 3.35 (dd,1H, J=6.3 and 15.9 Hz), 1.34 (d, 6H, J=5.7 Hz); ¹⁹F NMR (CDCl₃): −47664;LCMS: ret. time: 23.78 min.; purity: 95%; MS (m/e): 439 (MH⁺).

7.3.2325-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926699)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3-hydroxyphenyl)-5-fluoro-4-pyrimidineamine and4-[2-(N-morpholino)ethyleneoxy]aniline were reacted to yield5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.34 (s, 1H), 9.17 (bs, 1H), 8.95 (bs, 1H), 8.02 (d,1H, J=3.3 Hz), 7.53 (d, 2H, J=9.0 Hz), 7.28-7.23 (m, 1H), 7.12-7.04 (m,2H, 6.79 (d, 2H, J=9.0 Hz), 6.47 (dd, 1H, J=1.2 and 5.7 Hz), 4.00 (t,2H, J=6.0 Hz), 3.56 (t, 4H, J=4.5 Hz), 2.64 (t, 2H, J=6.0 Hz), 2.44 (t,4H, J=4.5 Hz); ¹⁹F NMR (DMSO-d6): −46715; LCMS: ret. time: 12.66 min.;purity: 95%; MS (m/e): 426 (MH⁺).

7.3.233N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926709)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-[2-(N-morpholino)ethyleneoxy]aniline were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.80 (d, 1H, J=3.6 Hz), 7.72 (bs, 1H), 7.62 (bs, 1H),7.41 (d, 1H, J=9.3 Hz), 7.24 (d, 1H, J=5.4 Hz), 7.05 (dd, 1H, J=2.4 and8.7 Hz), 6.84 (d, 2H, J=8.7 Hz), 6.75 (d, 1H, J=9.0 Hz), 4.24 (bs, 4H),4.11 (t, 2H, J=5.4 Hz), 3.74-3.69 (m, 4H), 2.80 (t, 2H, J=5.4 Hz),2.62-2.58 (m, 4H); ¹⁹F NMR (CD₃OD): −47912; LCMS: ret. time: 15.16 min.;purity: 91%; MS (m/e): 468 (MH⁺).

7.3.2345-Fluoro-N2-(3-hydroxyphenyl)-N4-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926710)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-4-pyrimidineamineand 3-aminophenol were reacted to yield5-fluoro-N2-(3-hydroxyphenyl)-N4-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.84 (d, 1H, J=4.2 Hz), 7.60 (d, 1H. J=9.3 Hz), 7.09(t, 1H, J=2.4 Hz), 7.04-6.96 (m, 2H), 6.93 (d, 2H, J=9.3 Hz), 6.40 (dt,1H, J=1.8 and 7.5 Hz), 4.15 (t, 2H, J=5.4 Hz), 3.75-3.70 (m, 4H), 2.81(t, 2H, J=5.1 Hz), 2.63-2.59 (m, 4H); LCMS: ret. time: 14.16 min.;purity: 98%; MS (m/e): 426 (MH⁺).

7.3.235N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926711)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-4-pyrimidineamineand 3,4-ethylenedioxyaniline were reacted to yieldN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.80 (d, 1H, J=4.2 Hz), 7.56 (d, 2H, J=8.7 Hz), 7.13(d, 1H, J=2.4 Hz), 6.91 (d, 2H, J=9.6 Hz), 6.86 (dd, 1H, J=2.4 and 9.0Hz), 6.67 (d, 1H, J=9.0 Hz), 4.23-4.18 (m, 4H), 4.14 (t, 3H, J=5.4 Hz),3.74-3.70 (m, 4H), 2.82 (t, 3H, J=5.4 Hz), 2.64-2.59 (m, 4H); ¹⁹F NMR(CDCl₃): −47914; LCMS: ret. time: 15.97 min.; purity: 94%; MS (m/e): 468(MH⁺).

7.3.236N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(tetrahydro-(1H)-pyrrol-1-ylsulfonyl)phenyl]-2,4-pyrimidinediamine(R926716)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-(tetrahydro-(1H)-pyrrol-1-ylsulfonyl)aniline were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[4-(tetrahydro-(1H)-pyrrol-1-ylsulfonyl)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.11 (bs, 1H), 9.76 (bs, 1H), 8.19 (d, 1H, J=3.9Hz), 7.82 (d, 2H, J=8.7 Hz), 7.62 (d, 2H, J=8.7 Hz), 7.27 (d, 1H, J=2.4Hz), 7.08 (dd, 1H, J=2.4 and 8.7 Hz), 6.85 (d, 1H, J=8.7 Hz), 4.23 (s,4H), 3.10-3.06 (m, 4H), 1.64-1.58 (m, 4H); LCMS: ret. time: 22.68 min.;purity: 93%; MS (m/e): 472 (MH⁺).

7.3.237N2-[3-[4-(2-Chloro-6-fluorobenzyl)piperazino]propyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926717)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3-[4-(2-chloro-6-fluorobenzyl)piperazino]propylamine were reacted toyieldN2-[3-[4-(2-chloro-6-fluorobenzyl)piperazino]propyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.79 (d, 1H, J=3.0 Hz), 7.37 (d, 1H, J=2.4 Hz),7.19-7.15 (m, 2H), 7.00-6.93 (m, 2H), 6.81 (d, 1H, J=8.7 Hz), 6.56 (d,1H, J=2.7 Hz), 5.48 (bs, 1H), 4.27-4.21 (m, 4H), 3.70 (d, 2H, J=1.8 Hz),3.36 (q, 2H, J=6.3 Hz), 2.68-2.35 (m, 10H), 1.75 (q, 2H, J=6.3 Hz); ¹⁹FNMR (CDCl₃): −31693,−48483; LCMS: ret. time: 18.20 min.; purity: 97%; MS(m/e): 532 (MH⁺).

7.3.238N2-(4-tert-Butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine(R926719)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-(4-tert -butylphenyl]-2-chloro-5-fluoro-4-pyrimidineamine and5-amino-2,3-dihydro-2-(methoxycarbonyl)benzofuran were reacted to yieldN2-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.16 (bs, 1H), 9.84 (bs, 1H), 8.16 (d, 1H, J=5.4Hz), 7.56 (d, 2H, J=8.1 Hz), 7.49 (s, 1H), 7.35 (d, 2H, J=8.7 Hz), 7.13(dd, 1H, J=1.8 and 8.7 Hz), 6.78 (d, 1H, J=8.7 Hz), 5.35 (dd, 1H, J=6.6and 10.5 Hz), 3.52 (dd, 1H, J=10.5 and 16.5 Hz), 3.20 (dd, 1H, J=6.6 and16.5 Hz), 1.27 (s, 9H); LCMS: ret. time: 26.52 min.; purity: 96%; MS(m/e): 437 (MH⁺).

7.3.239N4-[(5-Chloro-1-benzothiophen-3-yl)methyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926721)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(5-chloro-1-benzothiophen-3-yl)methyl]-5-fluoro-4-pyrimidineamineand 3,4-ethylenedioxyaniline were reacted to yieldN4-[(5-chloro-1-benzothiophen-3-yl)methyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 8.08 (d, 1H, J=1.8 Hz), 8.02 (d, 1H, J=8.7 Hz), 7.97(d, 1H, J=4.8 Hz), 7.63 (s, 1H), 7.42 (dd, 1H, J=1.8 and 9.3 Hz), 7.07(bs, 1H), 6.85 (dd, 1H, J=2.4 and 8.7 Hz), 6.56 (d, 1H, J=8.7 Hz), 4.77(s, 1H), 4.75 (s, 1H), 4.14 (s, 4H); LCMS: ret. time: 25.89 min.;purity: 97%; MS (m/e): 444 (MH⁺).

7.3.240N4-[(5-Chloro-1-benzothiophen-3-yl)methyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926722)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(5-chloro-1-benzothiophen-3-yl)methyl]-5-fluoro-4-pyrimidineamineand 3-aminophenol were reacted to yieldN4-[(5-chloro-1-benzothiophen-3-yl)methyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.47 (bs, 1H), 9.33 (bs, 1H), 8.78 (bs, 1), 8.11 (d,1H, J=2.1 Hz), 8.02 (d, 1H, J=J=8.7 Hz), 7.98 (d, 1H, J=4.5 Hz), 7.69(s, 1H), 7.41 (dd, 1H, J=1.8, 8.1 Hz), 7.07 (bs, 1H), 6.92 (d, 1H, J=8.4Hz), 6.82 (t, 1H, J=8.1 Hz), 6.34 (d, 1H, J=6.9 Hz), 4.80 (s, 1H), 4.78(s, 1H); LCMS: ret. time: 23.32 min.; purity: 93%; MS (m/e): 402 (MH⁺).

7.3.241N4-[2-[(2-Chloro-6-fluorobenzyl)thio]ethyl]-N2-(3,4-ethylenedioxy)-5-fluoro-2,4-pyrimidinediamine(R926723)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[2-[(2-chloro-6-fluorobenzyl)thio]ethyl]-5-fluoro-4-pyrimidineamineand 1,4-benzodioxan-6-amine were reacted to yieldN4-[2-[(2-chloro-6-fluorobenzyl)thio]ethyl]-N2-(3,4-ethylenedioxy)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.09 (bs, 1H), 7.94 (bs, 1H), 7.87 (d, 1H, J=4.2Hz), 7.34-7.30 (m, 2H), 7.24-7.18 (m, 2H), 7.01 (dd, 1H, J=2.4 and 8.7Hz), 6.68 (d, 1H, J=8.7 Hz), 4.11 (s, 4H), 3.83 (d, 2H, J=1.2 Hz),3.63-3.56 (m, 2H), 2.74 (t, 2H, J=7.5 Hz); LCMS: ret. time: 25.17 min.;purity: 92%; MS (m/e): 466 (MH⁺).

7.3.242N2-(2,3-Dihydro-1,4-benzodioxin-6-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945168)

In a manner analogous to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and2,3-dihydro-1,4-benzodioxin-6-ylmethylamine gaveN2-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃) δ 4.24 (s, 4H), 4.45 (d, J=6.0 Hz, 2H), 6.55 (ddd, J=0.9,2.4 and 8.4 Hz, 1H), 6.66 (d, 1H), 6.84 (m, 4H), 6.90 (m, 1H), 7.14 (t,J=8.1 Hz, 1H), 7.30 (m, 1H), 7.86 (d, J=3.3 Hz, 1H); ¹⁹F NMR (282 MHz,CDCl₃) δ −170.44; LCMS: ret. time: 18.33 min.; purity: 96.75%; MS (m/e):369.03 (MH⁺).

7.3.243N4-[2-[(2-Chloro-6-fluorobenzyl)thio]ethyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926724)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[2-[(2-chloro-6-fluorobenzyl)thio]ethyl]-5-fluoro-4-pyrimidineamineand 3-aminophenol were reacted to yieldN4-[2-[(2-chloro-6-fluorobenzyl)thio]ethyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (methyl sulfoxide-d₆): δ 9.76 (bs, 1H), 9.42 (bs, 1H), 8.70 (bs,1H), 8.02 (d, 1H, J=5.1 Hz), 7.33-7.30 (m, 2H), 7.24-7.18 (m, 1H),7.08-6.96 (m, 2H), 6.42 (d, 1H, J=4.6 Hz), 3.82 (d, 2H, J=1.2 Hz),3.68-3.61 (m, 2H), 2.77 (t, 2H, J=7.2 Hz); LCMS: ret. time: 23.00 min.;purity: 93%; MS (m/e): 424 (MH⁺).

7.3.244N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-phenyl-5-methylisoxazol-4-yl)-2,4-pyrimidinediamine(R926743)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and5-methyl-3-phenyl-4-isoxazolamine were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-phenyl-5-methylisoxazol-4-yl)-2,4-pyrimidinediamine.LCMS: ret. time: 20.90 min.; purity: 96%; MS (m/e): 420 (MH⁺).

7.3.245N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3,5-dimethylisoxazol-4-yl)-2,4-pyrimidinediamine(R926744)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3,5-dimethyl-4-isoxazolamine were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3,5-dimethylisoxazol-4-yl)-2,4-pyrimidinediamine.LCMS: ret. time: 18.89 min.; purity: 98%; MS (m/e): 358 (MH⁺).

7.3.246N2-[2-(Ethoxycarbonylmethylenethio)pyridin-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926727)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and5-amino-2-(ethoxycarbonylmethylenethio)pyridine were reacted to yieldN2-[2-(ethoxycarbonylmethylenethio)pyridin-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.30 (s, 1H), 9.22 (s, 1H), 8.62 (d, 1H, J=2.4 Hz),8.06-8.01 (m, 2H), 7.25 (d, 1H, J=2.4 Hz), 7.18-7.14 (m, 2H), 6.80 (d,1H, J=6.0 Hz), 4.22 (bs, 4H), 4.07 (q, 2H, J=6.9 Hz), 3.95 (s, 2H), 1.14(t, 3H, J=6.9 Hz); LCMS: ret. time: 21.60 min.; purity: 97%; MS (m/e):458 (MH⁺).

7.3.247N2-[2-(Ethoxycarbonylmethyleneoxy)pyridin-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926740)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and5-amino-2-(ethoxycarbonylmethyleneoxy)pyridine were reacted to yieldN2-[2-(ethoxycarbonylmethyleneoxy)pyridin-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.54 (bs, 1H), 9.14 (bs, 1H), 8.05 (s, 1H), 7.88 (d,1H, J=2.4 Hz), 7.54 (dd, 1H, J=2.7 and 10.2 Hz), 7.22 (d, 1H, J=1.8 Hz),7.10 (dd, 1H, J=1.8 and 8.7 Hz), 6.75 (d, 1H, J=9.0 Hz), 6.40 (d, 1H,J=9.9 Hz), 4.55 (s, 2H), 4.20 (bs, 4H), 4.10 (q, 2H, J=7.2 Hz), 1.18 (t,2H, J=7.2 Hz).

7.3.2485-Bromo-N2-(3,4-ethylenedioxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R925797)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,5-bromo-2-chloro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3,4-ethylenedioxyaniline were reacted to yield5-bromo-N2-(3,4-ethylenedioxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 9.33 (s, 1H), 9.06 (s, 1H), 8.34 (s, 1H), 8.14 (s,1H), 7.13-7.06-(m, 4H), 6.94 (bs, 1H), 6.61 (d, 1H, J=8.7 Hz), 6.54-6.50(m, 1H), 4.17-4.13 (m, 4H); LCMS: ret. time: 20.01 min.; purity: 93%; MS(m/e): 416 (MH⁺).

7.3.249 N2-Allyl-5-bromo-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R925822)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,5-bromo-2-chloro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and allylaminewere reacted to yieldN2-allyl-5-bromo-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ 8.08 (s, 1H), 7.21 (t, 1H, J=8.1 Hz), 7.02-6.97 (m, 2H), 6.71(dd, 1H, J=2.4 and 8.7 Hz), 5.91-5.77 (m, 1H), 5.19-5.09 (m, 2H),3.94-3.89 (m, 2H); LCMS: ret. time: 18.33 min.; purity: 99%; MS (m/e):322 (MH⁺).

7.3.2505-Cyano-N2-(3,4-ethylenedioxyphenyl)-N4-(methoxycarbonylbenzyl)-2,4-pyrimidinediamine(R925820)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-cyano-N4-(methoxycarbonylbenzyl)-4-pyrimidineamine and3,4-ethylenedioxyaniline were reacted to yield5-cyano-N2-(3,4-ethylenedioxyphenyl)-N4-(methoxycarbonylbenzyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.23 (s, 1H), 7.41-7.32 (m, 5H), 7.01 (d, 1H, J=3.0Hz), 6.86-6.71 (m, 3H), 6.54 (bs, 1H), 5.48 (d, 1H, J=6.3 Hz), 4.31 (bs,4H), 3.68 (s, 3H); LCMS: ret. time: 25.53 min.; purity: 97%; MS (m/e):418 (MH⁺).

7.3.251 (R935172):N4-[4-[Ethoxycarbonyl(dimethyl)methyl]phenyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-5-fluoro-4-pyrimidineamineand 3,4-ethylenedioxyaniline were reacted to produceN4-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.31 (s, 1H), 8.97 (s, 1H), 8.03 (d, 1H, J=3.5 Hz),7.70 (d, 2H, J=8.8 Hz), 7.29 (d, 1H, J=2.3 Hz), 7.23 (d, 2H, J=8.8 Hz),6.98 (dd, 1H, J=2.1 and 8.8 Hz), 6.66 (d, 1H, J=8.2 Hz), 4.19-4.15 (m,4H), 4.07 (qt, 2H, J=7.0 Hz), 1.48 (s, 6H), 1.10 (t, 3H, J=7.0 Hz).LCMS: ret. time: 24.51 min.; purity: 100%; MS (m/e): 453 (MH⁺).

7.3.252 (R935173):N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine

In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-pyrimidine-2,4-diamine,N4-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediaminewas reduced with DIBALH to giveN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.23 (s, 1H), 8.94 (s, 1H), 8.01 (d, 1H, J=3.5 Hz),7.63 (d, 2H, J=8.8 Hz), 7.31-7.27 (m, 3H), 6.98 (dd, 1H, J=2.9 and 8.8Hz), 6.65 (d, 1H, J=8.8 Hz), 4.65 (t, 1H, J=5.3 Hz), 4.17-4.16 (m, 4H),3.39 (d, 2H, J=5.2 Hz), 1.20 (s, 6H). 8.9 Hz), LCMS: ret. time: 19.52min.; purity: 100%; MS (m/e): 411 (MH⁺).

7.3.253 R935182:5-Fluoro-N2-[4-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3,4-propylenedioxyphenyl)-4-pyrimidineamine and4-(methoxycarbonylmethyleneoxy)aniline were reacted to produce5-fluoro-N2-[4-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.16 (s, 1H), 9.01 (s, 1H), 8.10 (d, 1H, J=4.1 Hz),7.51 (d, 2H, J=8.8 Hz), 7.37 (d, 1H, J=2.9 Hz), 7.32 (dd, 1H, J=2.9 and8.8 Hz), 6.98 (d, 1H, J=8.3 Hz), 6.80 (d, 2H, J=8.3 Hz), 4.70 (s, 2H),4.12-4.05 (app qt, 4H, J=5.3 Hz), 3.68 (s, 3H), 2.07 (q, 2H, J=5.3 Hz);LCMS: ret. time: 20.51 min.; purity: 97%; MS (m/e): 441 (MH⁺).

7.3.254 R935185:5-Fluoro-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3,4-propylenedioxyphenyl)-4-pyrimidineamine and3-(methoxycarbonylmethyleneoxy)aniline were reacted to produce5-fluoro-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.22 (s, 1H), 9.18 (s, 1H), 8.07 (d, 1H, J=3.5 Hz),7.41-7.35 (m, 2H), 7.32-7.28 (m, 2H), 7.09 (t, 1H, J=8.2 Hz), 6.90 (d,1H, J=8.2 Hz), 6.43 (dd, 1H, J=2.3 and 8.8 Hz), 4.65 (s, 2H), 4.11-4.04(app q, 4H, J=5.3 Hz), 3.67 (s, 3H), 2.06 (q, 2H, J=5.3 Hz); LCMS: ret.time: 20.57 min.; purity: 97%; MS (m/e): 441 (MH⁺).

7.3.255 R935187:N4-[3-(1-Bis(ethoxycarbonyl)ethoxy)phenyl]-5-fluoro-N2-[4-isopropoxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-isopropoxyphenyl)-4-pyrimidineamine and3-[1-bis(ethoxycarbonyl)ethoxy]aniline were reacted to provideN4-[3-(1-bis(ethyloxycarbonyl)ethoxy)phenyl]-5-fluoro-N2-[4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.08 (s, 1H), 9.98 (s, 1H), 8.19 (d, 1H, J=4.7 Hz),7.55 (d, 2H, J=8.8 Hz), 7.25 (d, 1H, J=8.8 Hz), 7.15 (d, 1H, J=8.3 Hz),7.13 (d, 1H, J=8.3 Hz), 6.91 (d, 2H, J=8.8 Hz), 6.51 (dd, 1H, J=1.7 and8.3 Hz), 4.56 (q, 1H, J=5.8 Hz), 4.19 (qt, 4H, J=7.0 Hz), 1.61 (s, 3H),1.23 (d, 6H, J=5.8 Hz), 1.14 (t, 6H, J=7.0 Hz); LCMS: ret. time: 15.23min.; purity: 94%; MS (m/e): 527 (MH⁺).

7.3.256 R935190:N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and6-aminoindazole were reacted to produceN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.69 (s, 1H), 9.62 (s, 1H), 8.14 (d, 1H, J=4.7 Hz),7.93 (s, 1H), 7.92 (s, 1H), 7.60 (d, 1H, J=8.8 Hz), 7.33-7.31 (m 1H),7.24 (dd, 2H, J=1.7 and 8.8 Hz), 6.79 (d, J=8.8 Hz), 4.20 (s, 4H); LCMS:ret. time: 17.66 min.; purity: 99%; MS (m/e): 379 (MH⁺).

7.3.257 R935191:5-Fluoro-N4-(3-hydroxyphenyl)-N2-(indazolin-6-yl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine and5-aminoindazole were reacted to give 5-fluoroN4-(3-hydroxyphenyl)-N2-(indazolin-6-yl)-2,4-pyrimidinediamine. ¹H NMR(DMSO-d6): δ 9.74 (s, 1H), 9.66 (s, 1H), 8.18 (d, 1H, J=4.1 Hz), 7.95(s, 1H), 7.93 (s, 1H), 7.59 (d, 1H, J=8.8 Hz), 7.33-7.26 (m, 2H),7.12-7.07 (m, 2H), 6.52 (dd, 1H, J=2.3 and 8.2 Hz); LCMS: ret. time:15.27 min.; purity: 99%; MS (m/e): 337 (MH⁺).

7.3.258 R935193:N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3,4-ethylenedioxyphenyl)-4-pyrimidineamime and1-methyl-5-aminoindazole were reacted to giveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.42 (s, 2H), 8.25 (d, 1H, J=5.2 Hz), 7.92 (s, 1H),7.86 (app s, 1H), 7.61 (d, 1H, J=8.8 Hz), 7.38 (dd, 1H, J=2.3 and 9.3Hz), 7.21 (d, 1H, J=2.3 Hz), 7.09 (dd, 1H, J=2.3 and 8.8 Hz). 6.79 (d,1H, J=8.8 Hz), 4.20 (s, 4H), 4.02 (s, 3H); LCMS: ret. time: 19.09 min.;purity: 99%; MS (m/e): 393 (MH⁺).

7.3.259 R935194:5-Fluoro-N4-(3-hydroxyphenyl)-N2-(1-methy-indazoline-5-yl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with1-methyl-5-aminoindazole to produce5-fluoro-N4-(3-hydroxyphenyl)-N2-(1-methy-indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.56 (s, 1H), 10.49 (s, 1H), 8.29 (d, 1H, J=5.2Hz), 7.98 (d, 1H, J=1.7 Hz), 7.92 (s, 1H), 7.59 (d, 1H, J=8.8 Hz), 7.36(dd, 1H, J=1.7 and 8.8 Hz), 7.10 (br m, 3H), 6.66 (td, 1H, J=1.7 and 7.0Hz), 4.01 (s, 3H). LCMS: ret. time: 16.62 min.; purity: 98%; MS (m/e):351 (MH⁺).

7.3.260 R935197:5-Fluoro-N2-(indazoline-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-isopropoxyphenyl)-4-pyrimidineamine was reactedwith 5-aminoindazoline to produce5-fluoro-N2-(indazoline-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.96 (s, 1H), 9.76 (s, 1H), 8.12 (d, 1H, J=4.6 Hz),7.94 (s, 1H), 7.92 (s, 1H), 7.53 (d, 2H, J=9.8 Hz), 7.46 (d, 1H, J=8.8Hz), 7.34 (dd, 1H, J=1.7 and 9.8 Hz), 6.83 (d, 2H, J=9.8 Hz), 4.55 (q,1H, J=5.8 Hz), 1.24 (d, 6H, J=5.8 Hz). LCMS: ret. time: 18.96 min.;purity: 100%; MS (m/e): 379 (MH⁺).

7.3.261 R935198:N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3,4-ethylenedioxyphenyl)-4-pyrimidineamime and5-aminoindazole were reacted to giveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.91 (s, 1H), 9.82 (s, 1H), 8.13 (d, 1H, J=4.6 Hz),7.94 (app s, 2H), 7.47 (d, 1H, J=8.8 Hz), 7.36 (dd, 1H, J=1.7 and 8.8Hz), 7.23 (d, 1H, J=2.3 Hz), 7.13 (dd, 1H, J=2.3 and 8.8 Hz), 6.76 (d,1H, J=8.8 Hz), 4.20 (s, 4H); LCMS: ret. time: 16.17 min.; purity: 99%;MS (m/e): 379 (MH⁺).

7.3.262 R935199:5-Fluoro-N4-(3-hydroxyphenyl)-N2-(indazoline-5-yl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamime and5-aminoindazole were reacted to give5-fluoro-N4-(3-hydroxyphenyl)-N2-(indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.78 (s, 1H), 9.68 (s, 1H), 9.49 (br s, 1H), 8.13(d, 1H, J=4.6 Hz), 8.06 (s, 1H), 7.93 (s, 1H), 7.50 (d, 1H, J=8.8 Hz),7.38 (dd, 1H, J=1.7 and 8.8 Hz), 7.17 (d, 1H, J=8.2 Hz), 7.11-7.06 (m,2H), 6.57 (dd, 1H, J=1.1 and 8.2 Hz). LCMS: ret. time: 13.79 min.;purity: 96%; MS (m/e): 337 (MH⁺).

7.3.263 R935203:5-Fluoro-N2-(4-isopropoxyphenyl)-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1-methyl-indazoline-5-yl)-4-pyrimidineamine and4-isopropoxyaniline were reacted to produce5-fluoro-N2-(4-isopropoxyphenyl)-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.57 (s, 1H), 10.12 (s, 1H), 8.24 (d, 1H, J=5.3Hz), 8.04 (s, 1H), 7.95 (s, 1H), 7.63 (d, 1H, J=9.3 Hz), 7.55 (dd, 1H,J=1.7 and 8.8 Hz), 7.30 (d, 2H, J=9.4 Hz), 6.82 (d, 2H, J=8.8 Hz), 4.53(q, 1H, J=6.4 Hz), 4.02 (s, 3H), 1.22 (d, 6H, J=6.4 Hz). LCMS: ret.time: 20.56 min.; purity: 99%; MS (m/e): 393 (MH⁺).

7.3.264 R935204:5-Fluoro-N2-(3-hydroxyphenyl)-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1-methyl-indazoline-5-yl)-4-pyrimidineamine and3-aminophenol were reacted to produce5-fluoro-N2-(3-hydroxyphenyl)-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine.LCMS: ret. time: 15.55 min.; purity: 98%; MS (m/e): 351 (MH⁺).

7.3.265 R935207:N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-methoxycarbonyl-fur-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine wasreacted with 4-(4-aminophenoxymethyl)-2-methoxycarbonyl-furan to giveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-methoxycarbonyl-fur-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.48 (s, 1H), 9.41 (s, 1H), 8.08 (d, 1H, J=3.4 Hz),7.37-7.10 (m, 6H), 6.74 (d, 2H, J=8.2 Hz), 6.61 (d, 1H, J=8.2 Hz), 5.00(s, 2H), 4.19 (br s, 4H), 3.79 (s, 3H). LCMS: ret. time: 22.85 min.;purity: 97%; MS (m/e): 493 (MH⁺).

7.3.266 R935208:N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine wasreacted with 6-amino-1-(methoxycarbonyl)methyl-indazoline to produceN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.39 (s, 1H), 9.19 (s, 1H), 8.08 (d, 1H, J=3.5 Hz),7.95 (s, 1H), 7.91 (s, 1H), 7.56 (d, 1H, J=8.2 Hz), 7.32 (d, 2H, J=8.9Hz), 7.22 (dd, 1H, J=2.9 and 8.2 Hz), 6.78 (d, 1H, J=8.8 Hz), 5.06 (s,2H), 4.21 (s, 4H), 3.61 (s, 3H). LCMS: ret. time: 19.39 min.; purity:93%; MS (m/e): 451 (MH⁺).

7.3.267 R935209:5-Fluoro-N2-[4-(methoxycarbonylmethyleneoxy)phenyl]-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1-methyl-indazoline-5-yl)-4-pyrimidineamine and4-(methoxycarbonylmethyleneoxy)aniline were reacted to provide5-fluoro-N2-[4-(methoxycarbonylmethyleneoxy)phenyl]-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.31 (s, 1H), 8.99 (s, 1H), 8.17 (s, 1H), 8.02 (d,1H, J=3.5 Hz), 7.92 (s, 1H), 7.59 (s, 2H), 7.50 (d, 2H, J=8.8 Hz), 6.73(d, 2H, J=8.8 Hz), 4.69 (s, 2H), 4.03 (s, 3H), 3.68 (s, 3H). LCMS: ret.time: 17.60 min.; purity: 99%; MS (m/e): 423 (MH⁺).

7.3.268 R935214:5-Fluoro-N2-(3,5-dimethoxyphenyl)-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1-methyl-indazoline-5-yl)-4-pyrimidineamine and3,5-dimethoxyaniline were reacted to produce5-fluoro-N2-(3,5-dimethoxyphenyl)-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.34 (s, 1H), 9.09 (s, 1H), 8.20 (d, 1H, J=5.3 Hz),8.07 (d, 1H, J=3.5 Hz), 7.90 (s, 1H), 7.63-7.55 (m, 2H), 6.89 (d, 2H,J=1.7 Hz), 6.02 (t, 1H, J=2.3 Hz), 4.02 (s, 3H), 3.54 (s, 6H). LCMS:ret. time: 18.81 min.; purity: 97%; MS (m/e): 395 (MH⁺).

7.3.269 R935215:5-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with6-amino-1-(methoxycarbonyl)methyl-indazoline to produce5-fluoro-N4-(3-hydroxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine.LCMS: ret. time: 16.08 min.; purity: 90%; MS (m/e): 408 (MH⁺).

7.3.270 R935218:5-Fluoro-N2-(4-isopropoxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-4-pyrimidineaminewas reacted with 4-isopropoxyaniline to provide5-fluoro-N2-(4-isopropoxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.47 (s, 1H), 8.99 (s, 1H), 8.10 (s, 1H), 8.07 (d,1H, J=4.1 Hz), 8.02 (s, 1H), 7.68 (d, 1H, J=8.8 Hz), 7.50-7.46 (m, 3H),6.74 (d, 2H, 8.8 Hz), 5.26 (s, 2H), 4.47 (q, 1H, J=5.8 Hz), 3.62 (s,3H), 1.21 (d, 6H, J=5.8 Hz). LCMS: ret. time: 21.76 min.; purity: 97%;MS (m/e): 451 (MH⁺).

7.3.271 R935219:N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-4-pyrimidineaminewas reacted with 3,4-ethylenedioxyaniline to provideN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.48 (s, 1H), 9.01 (s, 1H), 8.10 (s, 1H), 8.09 (d,1H, J=3.5 Hz), 8.01 (s, 1H), 7.68 (d, 1H, J=8.8 Hz), 7.48-7.43 (m, 1H),7.29 (d, 1H, J=2.3 Hz), 6.99 (d, 1H, J=2.3 and 8.2 Hz), 6.67 (dd, 1H,J=2.3 and 8.8 Hz), 5.27 (s, 2H), 4.15 (s, 4H), 3.62 (s, 3H). LCMS: ret.time: 18.99 min.; purity: 93%; MS (m/e): 451 (MH⁺).

7.3.272 R935220:5-Fluoro-N2-(3-hydroxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-4-pyrimidineaminewas reacted with 3-aminophenol to provide5-fluoro-N2-(3-hydroxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.51 (s, 1H), 9.19 (s, 1H), 9.10 (s, 1H), 8.21 (s,1H), 8.12 (d, 1H, J=3.5 Hz), 8.02 (s, 1H), 7.68 (d, 1H, J=8.8 Hz),7.49-7.45 (m 1H), 7.16 (s, 1H), 7.09 (d, 1H, J=7.6 Hz), 6.95 (app t, 1H,J=7.6 and 8.2 Hz), 6.31 (dd, 1H, J=1.7 and 7.6 Hz), 5.29 (s, 2H), 3.62(s, 3H). LCMS: ret. time: 16.16 min.; purity: 97%; MS (m/e): 409 (MH⁺).

7.3.273N4-(3,4-Ethylenedioxyphenyl)-N2-(3-furanylmethylene)-5-fluoro-2,4-pyrimidinediamine(R950203)

In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3-aminomethylenefurane were reacted to giveN4-(3,4-ethylenedioxyphenyl)-N2-(3-furanylmethylene)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 19.99 min.; purity: 88.4%; MS (m/e): 343.07 (MH⁺).

7.3.274N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[(4-methoxyphenyloxy)ethyl]-2,4-pyrimidinediamine(R950204)

In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and2-(4-methoxyphenyloxy)ethyl amine were reacted to giveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[(4-methoxyphenyloxy)ethyl]-2,4-pyrimidinediamine.LCMS: ret. time: 22.74 min.; purity: 91.9%; MS (m/e): 413.05 (MH⁺).

7.3.275N2-[2,3-Dihydrobenzo[b]furan-5-ylmethyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950205)

In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and2,3-dihydrobenzo[b]furan-5-ylmethylamine were reacted to giveN2-[2,3-dihydrobenzo[b]furan-5-ylmethyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 21.43 min.; purity: 97.5%; MS (m/e): 395.05 (MH⁺).

7.3.276N2-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950206)

In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and2,3-dihydro-1,4-benzodioxin-2-ylmethylamine were reacted to giveN2-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 22.49 min.; purity: 87.6%; MS (m/e): 411.01 (MH⁺).

7.3.277N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(methylthio)-1,3-benzothiaz-6-yl]-2,4-pyrimidinediamine(R950201)

In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and2-(methylthio)-1,3-benzothiazol-6-amine were reacted to giveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(methylthio)-1,3-benzothiaz-6-yl]-2,4-pyrimidinediamine.LCMS: ret. time: 22.67 min.; purity: 76.9%; MS (m/e): 441.91 (MH⁺).

7.3.278N2-[2,3-Dihydrobenzo[b]furan-5-ylmethyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R950213)

In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and2,3-dihydrobenzo[b]furan-5-ylmethylamine were reacted toN2-[2,3-dihydrobenzo[b]furan-5-ylmethyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 17.80 min.; purity: 99.2%; MS (m/e): 353.08 (MH⁺).

7.3.279N2-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R950214)

In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and2,3-dihydro-1,4-benzodioxin-2-ylmethylamine were reacted to giveN2-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 19.26 min.; purity: 96.2%; MS (m/e): 369.08 (MH⁺).

7.3.2805-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(methylthio)-1,3-benzothiaz-6-yl)-2,4-pyrimidinediamine(R950212)

In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and2-(methylthio)-1,3-benzothiazol-6-amine were reacted to give5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(methylthio)-1,3-benzothiaz-6-yl)-2,4-pyrimidinediamine.LCMS: ret. time: 19.83 min.; purity: 98.9%; MS (m/e): 399.98 (MH⁺).

7.3.281N2-(3-Aminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R950227)

In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and1,3-diaminobenzene were reacted to giveN2-(3-aminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 11.89 min.; purity: 97.6%; MS (m/e): 312.05 (MH⁺).

7.3.282N2-(1,4-Benzoxazin-6-yl)]-5-fluoro-N4-(3-nitrophenyl)-2,4-pyrimidinediamine(R950253)

In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and6-amino-1,4-benzoxazine were reacted to giveN2-(1,4-benzoxazin-6-yl)]-5-fluoro-N4-(3-nitrophenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 18.52 min.; purity: 99.5%; MS (m/e): 382.93 (MH⁺).

7.3.283N2-(Ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R950215)

In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-ethoxycarbonylmethyleneaminophenylaniline were reacted toN2-(ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 18.90 min.; purity: 83.4%; MS (m/e): 398.06 (MH⁺).

7.3.284N2-(Ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine(R950229)

In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-ethoxycarbonylmethyleneaminophenylaniline were reacted toN2-(ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 16.37 min.; purity: 78.3%; MS (m/e): 441.03 (MH⁺).

7.3.2855-Cyano-N2-(3-hydroxyphenyl)-N4-(methoxycarbonylbenzyl)-2,4-pyrimidinediamine(R925821)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-cyano-N4-(methoxycarbonylbenzyl)-4-pyrimidineamine and3-hydroxyaniline were reacted to yield5-cyano-N2-(3-hydroxyphenyl)-N4-(methoxycarbonylbenzyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.27 (s, 1H), 7.38-7.28 (m, 5H), 7.19-7.07 (m, 2H),6.98-6.91 (m, 2H), 6.64 (d, 1H, J=6.6 Hz), 3.55 (s, 3H); LCMS: ret.time: 24.18 min.; purity: 98%; MS (m/e): 376 (MH⁺).

7.3.2865-Fluoro-N4-[2-fluoro-4-(methoxymethyleneoxy)phenyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926680)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(2-fluoro-4-methoxymethyleneoxyphenyl)-4-pyrimidineamineand 3-hydroxyaniline were reacted to yield5-fluoro-N4-(2-fluoro-4-methoxymethyleneoxyphenyl)-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.

7.3.287N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[(1H)-indol-5-yl]-2,4-pyrimidinediamine(R926748)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and5-aminoindole were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[(1H)-indol-5-yl]-2,4-pyrimidinediamine.LCMS: ret. time: 20.37 min.; purity: 97%; MS (m/e): 378 (MH⁺).

7.3.2885-Fluoro-N4-(3-hydroxyphenyl)-N2-[(1H)-indol-5-yl]-2,4-pyrimidinediamine(R926749)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and5-aminoindole were reacted to yield5-fluoro-N4-(3-hydroxyphenyl)-N2-[(1H)-indol-5-yl]-2,4-pyrimidinediamine.LCMS: ret. time: 17.31 min.; purity: 94%; MS (m/e): 366 (MH⁺).

7.3.289N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[(1H)-indol-6-yl]-2,4-pyrimidinediamine(R926750)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and6-aminoindole were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[(1H)-indol-6-yl]-2,4-pyrimidinediamine.LCMS: ret. time: 20.80 min.; purity: 91%; MS (m/e): 378 (MH⁺).

7.3.2905-Fluoro-N4-(3-hydroxyphenyl)-N2-[(1H)-indol-6-yl]-2,4-pyrimidinediamine(R926751)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and6-aminoindole were reacted to yield5-fluoro-N4-(3-hydroxyphenyl)-N2-[(1H)-indol-6-yl]-2,4-pyrimidinediamine.LCMS: ret. time: 18.13 min.; purity: 96%; MS (m/e): 336 (MH⁺).

7.3.291N4-[4-(Aminocarbonylmethyleneoxy)phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945063)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 3-hydroxyaniline (110 mg, 1 mmol) andN4-[4-(aminocarbonylmethyleneoxy)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine(80 mg, 0.27 mmol) gaveN4-[4-(aminocarbonylmethyleneoxy)phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(75 mg, 76%). ¹H NMR (acetone-d₆): δ 6 4.51 (s, 2H), 6.64 (dm, J=8.4 Hz,1H), 7.06-7.14 (m, 5H), 7.70 (dd, J=2.4 and 9.0 Hz, 2H), 8.27 (d, J=6.0Hz, 1H); ¹⁹F NMR (282 MHz, acetone-d6): δ −164.00; LCMS: ret. time:14.66 min.; purity: 88.63%; MS (m/e): 370.00 (MH⁺).

7.3.292N4-[4-(Cyanomethyleneoxy)phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945071)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-hydroxyaniline (94 mg, 0.86 mmol) and2-chloro-N4-[4-(cyanomethyleneoxy)phenyl]-5-fluoro-4-pyrimidineamine (80mg, 0.29 mmol) gaveN4-[4-(cyanomethyleneoxy)phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(65 mg, 64%) as a off-white solid. ¹H NMR (acetone-d₆): δ 5.16 (s, 2H),6.64 (ddd, J=1.8, 2.4 and 7.5 Hz, 1H), 7.03 (t, J=2.1 Hz, 1H), 7.08-7.16(m, 2H), 7.19 (d, J=9.3 Hz, 2H), 7.77 (d, J=9.3 Hz, 2H), 8.30 (d, J=5.4Hz, 1H), 10.04 (s, 1H, NH), 11.33 (s, 1H, NH); ¹⁹F NMR (282 MHz,acetone-d₆): δ −163.52; LCMS: ret. time: 17.08 min.; purity: 100%; MS(m/e): 352.13 (MH⁺).

7.3.293N4-(3-Cyanophenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945109)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-aminobenzonitrile (142 mg, 1.2 mmol) and2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gave2-chloro-N4-(3-cyanophenyl)-5-fluoro-4-pyrimidineamine (128 mg, 86%) asa white solid. The reaction of2-chloro-N4-(3-cyanophenyl)-5-fluoro-4-pyrimidineamine (50 mg, 0.2 mmol)and 3-aminophenol (66 mg, 0.6 mmol) gaveN4-(3-cyanophenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(40 mg, 62%). 1H NMR (acetone-d₆): δ 6.48 (ddd, J=0.9, 2.4 and 7.8 Hz,1H), 7.10 (t, J=8.1 Hz, 1H), 7.18 (ddd, J=1.2, 2.1 and 8.1 Hz, 1H), 7.33(t, J=2.1 Hz, 1H), 7.45 (dt, J=1.2 and 7.8 Hz, 1H), 7.54 (t, J=8.1 Hz,1H), 8.08 (d, J=3.3 Hz, 1H), 8.14 (ddd, J=1.5, 2.7 and 8.4 Hz, 1H), 8.39(t, J=2.1 Hz, 1H), 8.58 (s, 1H, NH), 8.84 (s, 1H, NH); ¹⁹F NMR (282 MHz,acetone-d₆): δ −167.41; LCMS: ret. time: 17.75 min.; purity: 92.39%; MS(m/e): 322.59 (MH⁺).

7.3.294N4-(3-Cyanophenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945110)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3-cyanophenyl)-5-fluoro-4-pyrimidineamine (50 mg, 0.2 mmol)and 4-(methoxycarbonylmethyleneoxy)aniline (109 mg, 0.6 mmol) gaveN4-(3-cyanophenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(30 mg, 38%). ¹H NMR (acetone-d₆): δ 3.74 (s, 3H), 4.72 (s, 2H), 6.93(d, J=9.0 Hz, 2H), 7.46 (dt, J=1.5 and 7.5 Hz, 1H), 7.54 (t, J=7.8 Hz,1H), 7.60 (dd, J=1.8 and 9.0 Hz, 2H), 8.03-8.07 (m, 2H), 8.43 (m, 1H),8.48 (br, 1H, NH), 8.80 (br, 1H, NH); ¹⁹F NMR (282 MHz, acetone-d₆): δ−168.2; LCMS: ret. time: 20.24 min.; purity: 94.79%; MS (m/e): 393.98(MH⁺).

7.3.2955-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(indol-3-yl)ethyl]-2,4-pyrimidinediamine(R945117)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine(50 mg, 0.21 mmol) and tryptamine (100 mg, 0.62 mmol) gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(indol-3-yl)ethyl]-2,4-pyrimidinediamine(40 mg, 53%). ¹H NMR (CD₃OD): δ 3.01 (t, J=7.2 Hz, 2H), 3.61 (t, J=7.2Hz, 2H), 6.51 (ddd, J=0.9, 2.1 and 8.1 Hz, 1H), 6.96 (td, J=0.9 and 7.2Hz, 1H), 7.03-7.09 (m, 3H), 7.22 (d, J=7.5 Hz, 1H), 7.28-7.32 (m, 2H),7.53 (d, J=7.8 Hz, 1H), 7.72 (d, J=4.5 Hz, 1H); ¹⁹F NMR (282 MHz,CD₃OD): δ −171.72; LCMS: ret. time: 20.17 min.; 95.66%; MS (m/e): 364.05(MH⁺).

7.3.2965-Fluoro-N4-(3-hydroxyphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945118)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine(80 mg, 0.33 mmol) and 3-methoxycarbonylmethyleneoxyaniline (180 mg,0.99 mmol) gave5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(130 mg). ¹H NMR (acetone-d₆): δ 3.74 (s, 3H), 4.64 (s, 2H), 6.71 (m,1H), 6.80 (m, 1H), 7.23-7.32 (m, 6H), 8.32 (d, J=5.1 Hz, 1H); LCMS: ret.time: 18.37 min.; purity: 100%; MS (m/e): 384.70 (MH⁺).

7.3.297N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945124)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (80 mg,0.28 mmol) and 3-methoxycarbonylmethyleneoxyaniline (154 mg, 0.85 mmol)gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(90 mg, 74%). ¹H NMR (CDCl₃): δ 3.80 (s, 3H), 4.27 (q, J=0.9 Hz, 4H),4.58 (s, 2H), 6.54 (ddd, J=0.9, 2.7 and 8.1 Hz, 1H), 6.65 (d, J=2.7 Hz,1H), 6.86 (d, J=8.7 Hz, 1H), 6.98 (dd, J=2.4 and 8.4 Hz, 1H), 6.98 (br,1H), 7.09 (ddd, J=1.2, 2.1 and 8.1 Hz, 1H), 7.18 (t, J=8.1 Hz, 1H), 7.24(d, J=2.4 Hz, 1H), 7.32 (t, J=2.1 Hz, 1H), 7.92 (d, J=3.3 Hz, 1H); ¹⁹FNMR (282 MHz, CDCl₃): δ −167.52; LCMS: ret. time: 21.64 min.; purity:98.07%; MS (m/e): 426.99 (MH⁺).

7.3.2985-Fluoro-N4-(4-isopropoxyphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945125)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine (80 mg, 0.28mmol) and methyl 3-aminophenoxyacete (154 mg, 0.85 mmol) gave5-fluoro-N4-(4-isopropoxyphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(80 mg, 66%). ¹H NMR (CDCl₃) δ 1.33 (s, 3H), 1.35 (s, 3H), 3.80 (s, 3H),4.52 (p, J=6.0 Hz, 1H), 4.55 (s, 2H), 6.53 (ddd, J=0.9, 2.4 and 8.1 Hz,1H), 6.69 (d, J=2.4 Hz, 1H), 6.90 (d, J=9.0 Hz, 2H), 7.04-7.08 (m, 2H),7.16 (t, J=8.1 Hz, 1H), 7.32 (t, J=2.1 Hz, 1H), 7.47 (d, J=8.7 Hz, 2H),7.92 (d, J=3.0 Hz, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ −167.64; LCMS: ret.time: 24.70 min.; purity: 100%; MS (m/e): 427.00 (MH⁺).

7.3.299N2-[4-(Aminocarbonylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945064)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-N2-(3-hydroxyphenyl))-5-fluoro-2,4-pyrimidinediamine,4-(aminocarbonylmethyleneoxy)aniline (198 mg, 1.2 mmol) and2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine (95 mg, 0.4mmol) gaveN2-[4-(aminocarbonylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(60 mg, 41%). ¹H NMR (CD₃OD): δ 4.55 (s, 2H), 6.75 (dm, J=7.5 Hz, 1H),7.08 (d, J=9.3 Hz, 2H), 7.18 (m, 2H), 7.22 (d, J=8.7 Hz, 1H), 7.46 (d,J=9.0 Hz, 2H), 8.09 (d, 1H); LCMS: ret. time: 14.38 min.; purity: 100%;MS (m/e): 370.00 (MH⁺).

7.3.3005-Fluoro-N2-(3-hydroxyphenyl)-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945132)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyaniline(490 mg, 2.4 mmol) and 2,4-dichloro-5-fluoropyrimidine (200 mg, 1.2mmol) gave2-chloro-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-4-pyrimidineamine.The reaction of2-chloro-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-4-pyrimidineamine(40 mg, 0.12 mmol) and 3-aminophenol (40 mg, 0.36 mmol) gave5-fluoro-N2-(3-hydroxyphenyl)-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(30 mg, 62%). ¹H NMR (CDCl₃): δ 2.61 (s, 3H), 5.21 (s, 2H), 6.50 (ddd,J=0.9, 2.4 and 7.8 Hz, 1H), 6.76 (ddd, J=0.6, 2.4 and 9.0 Hz, 1H),6.80-6.85 (m, 3H), 7.12 (t, J=8.1 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H),7.50-7.52 (m, 2H), 7.94 (d, J=3.3 Hz, 1H), 7.98 (t, J=2.4 Hz, 1H); ¹⁹FNMR (282 MHz, CDCl₃): δ −167.19; LCMS: ret. time: 18.88 min.; purity:100%; MS (m/e): 408.97 (MH⁺).

7.3.301N2-[4-(Aminocarbonylmethoxy)phenyl]-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945133)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-4-pyrimidineamine(30 mg, 0.09 mmol) and 4-(aminocarbonylmethyleneoxy)aniline (45 mg, 0.27mmol) gaveN2-[4-(aminocarbonylmethyleneoxy)phenyl]-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(10 mg, 24%). ¹H NMR (acetone-d₆): δ 2.62 (s, 3H), 4.43 (s, 2H), 5.19(s, 2H), 6.77 (ddd, J=1.2, 2.4 and 8.1 Hz, 1H), 6.94 (d, J=9.0 Hz, 2H),7.25 (t, J=8.1 Hz, 1H), 7.34 (ddd, J=0.9, 1.8, 9.0 Hz, 1H), 7.68 (d,J=9.0 Hz, 2H), 7.81 (t, J=2.1 Hz, 1H), 7.99 (d, J=3.6 Hz, 1H), 8.45 (br,1H, NH), 8.57 (br, 1H, NH); ¹⁹F NMR (282 MHz, acetone-d₆): δ −168.20;LCMS: ret. time: 16.80 min.; purity: 84.91%; MS (m/e): 466.05 (MH⁺).

7.3.302N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945128)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (40 mg,0.14 mmol) and 3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyaniline (87mg, 0.42 mmol) gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(30 mg, 47%). ¹H NMR (CDCl₃): δ 2.62 (s, 3H), 4.26 (q, J=2.1 Hz, 4H),5.09 (s, 2H), 6.63-6.67 (m, 2H), 6.85 (d, J=8.4 Hz, 1H), 6.95-6.99 (m,2H), 7.09 (dt, J=0.9 and 6.9 Hz, 1H), 7.19 (t, J=8.4 Hz, 1H), 7.23 (d,J=2.4 Hz, 1H), 7.42 (t, J=2.4 Hz, 1H), 7.92 (d, J=3.0 Hz, 1H); ¹⁹F NMR(282 MHz, CDCl₃): δ −167.47; LCMS: ret. time: 21.26 min.; purity:96.72%; MS (m/e): 451.01 (MH⁺).

7.3.3035-Fluoro-N4-(4-isopropoxyphenyl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945129)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine (40 mg, 0.14mmol) and 3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyaniline (87 mg,0.42 mmol) gave5-fluoro-N4-(4-isopropoxyphenyl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(40 mg, 63%). 1H NMR (CDCl₃): δ 1.32 (s, 3H), 1.34 (s, 3H), 2.61 (s,3H), 4.52 (p, J=6.0 Hz, 1H), 5.08 (s, 2H), 6.64 (ddd, J=1.2, 2.7 and 8.1Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.89 (d, J=9.0 Hz, 2H), 7.07-7.11 (m,2H), 7.16 (t, J=8.1 Hz, 1H), 7.38 (t, J=2.1 Hz, 1H), 7.46 (d, J=9.0 Hz,2H), 7.91 (d, J=3.3 Hz, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ −167.55; LCMS:ret. time: 24.49 min.; 96.15%; MS (m/e): 451.08 (MH⁺).

7.3.304N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945137)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-4-pyrimidineamine(40 mg, 0.12 mmol) and 3,4-ethylenedioxyaniline (55 mg, 0.36 mmol)reacted to giveN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 2.60 (s, 3H), 4.24 (q, J=2.7 Hz, 4H), 5.21 (s, 2H),6.74-6.78 (m, 2H), 6.81 (d, J=8.4 Hz, 1H), 6.90 (dd, J=1.2, 7.8 Hz, 1H),7.01 (dd, J=2.4 and 8.4 Hz, 1H), 7.22 (t, J=8.4 Hz, 1H), 7.30 (d, J=2.4Hz, 1H), 7.48 (br, 1H), 7.94 (d, J=3.3 Hz, 1H), 7.98 (br, 1H); ¹⁹F NMR(282 MHz, CDCl₃) δ −168.23; LCMS: ret. time: 21.20 min.; purity: 91.09%;MS (m/e): 450.99 (MH⁺).

7.3.3055-Fluoro-N2-(4-isopropoxyphenyl)-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945138)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-4-pyrimidineamine(40 mg, 0.12 mmol) and 4-isopropoxyaniline (55 mg, 0.36 mmol) gave5-fluoro-N2-(4-isopropoxyphenyl)-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 1.31 (s, 3H), 1.33 (s, 3H), 2.60 (s, 3H), 4.48 (p,J=6.0 Hz, 1H), 5.20 (s, 2H), 6.74-6.78 (m, 2H), 6.87 (d, J=9.0 Hz, 2H),6.92 (dd, J=1.2 and 8.4 Hz, 1H), 7.22 (t, J=8.4 Hz, 1H), 7.50 (m, 3H),7.94 (d, J=3.0 Hz, 2H); ¹⁹F NMR (282 MHz, CDCl₃): δ −168.46; LCMS: ret.time: 24.95 min.; purity: 73.74%; MS (m/e): 451.06 (MH⁺).

7.3.306N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945139)

Using general hydrogenation conditions, 2,6-dimethyl-4-nitrophenol wasreduced to 4-amino-2,6-dimethylphenol. In a manner analogous to thepreparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 4-amino-2,6-dimethylphenol (823 mg, 6 mmol) and2,4-dichloro-5-fluoropyrimidine (500 mg, 3 mmol) gave2-chloro-N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine.Compound2-chloro-N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine(500 mg, 1.87 mmol) and 3-(methoxycarbonylmethyleneoxy)aniline (500 mg,2.76 mmol) reacted to giveN4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(500 mg, 65%). ¹H NMR (CD₃OD): δ 2.16 (s, 6H), 3.76 (s, 3H), 4.51 (s,2H), 6.79 (ddd, J=0.9, 2.4 and 8.1 Hz, 1H), 7.01-7.06 (m, 2H), 7.15 (s,2H), 7.26 (t, J=8.1 Hz, 1H), 7.93 (d, J=5.7 Hz, 1H); ¹⁹F NMR (282 MHz,CD₃OD): δ −163.31; LCMS: ret. time: 20.44 min.; purity: 84.25%; MS(m/e): 413.03 (MH⁺).

7.3.307N4-(Benzothiophen-3-ylmethyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945146)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of benzothiophen-3-ylmethylamine (244 mg, 1.5 mmol) and2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gaveN4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine. Thereaction ofN4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine and3-aminophenol (200 mg, 1.83 mmol) gaveN4-(benzothiophen-3-ylmethyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.(40 mg, 36%). ¹H NMR (CDCl₃): δ 4.45 (br, 1H), 4.95 (dd, J=1.2 and 5.4Hz, 2H), 5.33 (br, 1H), 6.40 (ddd, J=1.2, 2.4 and 8.1 Hz, 1H), 6.85(ddd, J=0.9, 2.1 and 8.1 Hz, 1H), 6.91 (br, 1H), 7.05 (t, J=8.1 Hz, 1H),7.26 (m, 1H), 7.39-7.47 (m, 3H), 7.81 (dd, J=1.2 and 5.1 Hz, 1H), 7.84(d, J=3.3 Hz, 1H), 7.92 (m, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ −168.89;LCMS: ret. time: 21.91 min.; purity: 99.34%; MS (m/e): 366.96 (MH⁺).

7.3.3085-Fluoro-N2-(3-hydroxyphenyl)-N4-(3-pyridylmethyl)-2,4-pyrimidinediamine(R945147)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-pyridylmethylamine (162 mg, 1.5 mmol) and2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) were reacted to give2-chloro-5-fluoro-N4-(3-pyridylmethyl)-4-pyrimidineamine. Then2-chloro-5-fluoro-N4-(3-pyridylmethyl)-4-pyrimidineamine and3-aminophenol (200 mg, 1.83 mmol) reacted to give5-fluoro-N2-(3-hydroxyphenyl)-N4-(3-pyridylmethyl)-2,4-pyrimidinediamine(40 mg, 43%). ¹H NMR (CD₃OD): δ 4.71 (s, 2H), 6.38 (ddd, J=0.9, 2.4 and8.1 Hz, 1H), 6.88 (ddd, J=0.9, 2.1 and 8.1 Hz, 1H), 7.00 (t, J=8.1 Hz,1H), 7.14 (t, J=2.4 Hz, 1H), 7.37 (dd, J=4.8 and 7.8 Hz, 1H), 7.73 (d,J=3.6 Hz, 1H), 7.87 (dt, J=2.1 and 7.5 Hz, 1H), 8.39 (dd, J=1.2 and 7.8Hz, 1H), 8.57 (d, J=2.1 Hz, 1H); ¹⁹F NMR (282 MHz, CD₃OD): δ −170.99;LCMS: ret. time: 8.82 min.; purity: 92.90%; MS (m/e): 312.05 (MH⁺).

7.3.309N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945148)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-amino-2-chloro-6-methylphenol and 2,4-dichloro-5-fluoropyrimidineresulted2-chloro-N4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-4-pyrimidineamine.The reaction of2-chloro-N4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-4-pyrimidineamineand 3-methoxycarbonylmethyleneoxyaniline (1.95 g, 11 mmol) gaveN4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(850 mg, 55%). ¹H NMR (CD₃OD): δ 2.22 (s, 3H), 3.76 (s, 3H), 4.52 (s,2H), 6.50 (dt, J=2.7 and 6.3 Hz, 1H), 7.09-7.14 (m, 2H), 7.24 (t, J=1.8Hz, 1H), 7.30 (t, J=1.2 Hz, 1H), 7.49 (d, J=2.4 Hz, 1H), 7.88 (d, J=3.9Hz, 1H); ¹⁹F NMR (282 MHz, CD₃OD): δ −168.70; LCMS: ret. time: 20.63min.; purity: 98.56%; MS (m/e): 432.96 (MH⁺).

7.3.310N4-[(2,5-Dimethyl-3-furyl)methyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945151)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of (2,5-dimethyl-3-furyl)methylamine (188 mg, 1.5 mmol) and2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gave2-chloro-N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-4-pyrimidineamine.The reaction of2-chloro-N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-4-pyrimidineamineand 3-aminophenol (200 mg, 1.83 mmol) gaveN4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(50 mg, 51%). ¹H NMR (CDCl₃): δ 2.22 (s, 3H), 2.23 (s, 3H), 4.39 (d,J=5.1 Hz, 2H), 5.24 (br, 1H), 5.90 (s, 1H), 6.52 (d, J=6.6 Hz, 1H), 6.99(d, J=8.1 Hz, 1H), 7.13 (t, J=8.1 Hz, 1H), 7.29 (s, 1H), 7.71 (m, 2H);¹⁹F NMR (282 MHz, CDCl₃): δ −167.84; LCMS: ret. time: 19.83 min.;purity: 96.32%; MS (m/e): 329.05 (MH⁺).

7.3.311N4-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945153)

In a manner analogous to the preparation ofN2,N4-bis[3-methoxy-4-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine,the reaction of 2,6-dimethyl-4-nitrophenol (1.67 g, 10 mmol), potassiumcarbonate (13 g, 0.1 mol) and iodomethane (2.5 mL, 50 mmol) gave2,6-dimethyl-1-methoxy-4-nitrobenzene. Hydrogenation of2,6-dimethyl-1-methoxy-4-nitrobenzene gave3,5-dimethyl-4-methoxyaniline.

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,the reaction of 3,5-dimethyl-4-methoxyaniline (400 mg, 2.6 mmol) and2,4-dichloro-5-fluoropyrimidine (200 mg, 1.2 mmol) gave2-chloro-N4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine.The reaction of2-chloro-N4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-4-pyrimidineamineand 3-(methoxycarbonylmethyleneoxy)aniline (650 mg, 3.6 mmol) gaveN4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(180 mg, 35%). ¹H NMR (CD₃OD): δ 2.20 (s, 6H), 3.70 (s, 3H), 3.74 (s,3H), 4.52 (s, 2H), 6.76 (ddd, J=0.9, 2.4 and 8.4 Hz, 1H), 7.03-7.08 (m,2H), 7.24 (m, 3H), 7.96 (d, J=5.4 Hz, 1H); ¹⁹F NMR (282 MHz, CD₃OD): δ−162.92; LCMS: ret. time: 23.13 min.; purity: 100%; MS (m/e): 427.04(MH⁺).

7.3.312N4-[4-(N-Benzylpiperazino)phenyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945155)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidineamine,the reaction ofN4-[4-(N-benzylpiperazino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine(50 mg, 0.12 mmol) and 3,4-ethylenedioxyaniline (0.045 mL, 0.36 mmol)gaveN4-[4-(N-benzylpiperazino)phenyl)]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(40 mg, 63%). ¹H NMR (CDCl₃): δ 2.64 (t, J=4.8 Hz, 4H), 3.20 (t, J=4.8Hz, 4H), 3.59 (s, 2H), 4.24 (m, 4H), 6.61 (d, 1H, NH), 6.68 (br, 1H,NH), 6.76 (d, J=8.7 Hz, 1H), 6.88 (dd, J=2.4 and 8.7 Hz, 1H), 6.93 (d,J=8.7 Hz, 2H), 7.19 (d, J=2.4 Hz, 1H), 7.28-7.36 (m, 5H), 7.47 (d, J=8.7Hz, 2H), 7.87 (d, J=3.3 Hz, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ −168.66;LCMS: ret. time: 18.05 min.; purity: 100%; MS (m/e): 513.10 (MH⁺).

7.3.313N2-[(2,5-Dimethyl-3-furyl)methyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945162)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine(50 mg, 0.21 mmol) and (2,5-dimethyl-3-furyl)methylamine (80 mg, 0.63mmol) gaveN2-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(40 mg, 59%). ¹H NMR (acetone-d₆): δ 2.14 (s, 6H), 4.37 (d, J=4.2 Hz,2H), 5.96 (s, 1H), 6.77 (d, J=6.6 Hz, 1H), 7.23-7.28 (m, 2H), 7.44 (s,1H), 8.11 (d, J=4.8 Hz, 1H), 9.05 (br, 1H), 9.75 (br, 1H); ¹⁹F NMR (282MHz, acetone-d₆): δ −165.77; LCMS: ret. time: 19.23 min.; purity:94.89%; MS (m/e): 329.08 (MH⁺).

7.3.314N2-[4-(N-Benzylpiperazino)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945163)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylendioxyphenyl)-5-fluoro-4-pyrimidineamine (50 mg,0.18 mmol) and 4-(4-benzylpiperazino)aniline (142 mg, 0.53 mmol)resultedN2-[4-(N-benzylpiperazino)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(30 mg, 33%). ¹H NMR (CDCl₃): δ 2.63 (t, J=4.8 Hz, 4H), 3.16 (t, J=4.8Hz, 4H), 3.58 (s, 2H), 4.27 (m, 4H), 6.56 (d, 1H, NH), 6.70 (br, 1H,NH), 6.82 (d, J=8.7 Hz, 1H), 6.89 (d, J=9.0 Hz, 2H), 6.96 (dd, J=2.7 and8.7 Hz, 1H), 7.28 (d, J=2.7 Hz, 1H), 7.30-7.36 (m, 5H), 7.39 (d, J=8.7Hz, 2H), 7.88 (d, J=3.3 Hz, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ −168.94;LCMS: ret. time: 18.12 min.; purity: 98.42%; MS (m/e): 512.95 (MH⁺).

7.3.315N2-(Benzothiophen-3-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945164)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine(50 mg, 0.21 mmol) and benzothiophen-3-ylmethylamine (100 mg, 0.61 mmol)gaveN2-(benzothiophen-3-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(40 mg, 53%). ¹H NMR (CDCl₃): δ 4.82 (d, J=6.0 Hz, 2H), 6.45 (dd, J=8.1Hz, 1H), 6.70 (m, 1H), 6.80 (d, J=8.4 Hz, 1H), 7.03 (t, J=8.1 Hz, 1H),7.22 (m, 1H), 7.34 (s, 1H), 7.39-7.46 (m, 2H), 7.82 (m, 1H), 7.89-7.92(m, 2H); ¹⁹F NMR (282 MHz, CDCl₃): δ −170.02; LCMS: ret. time: 21.29min.; purity: 92.97%; MS (m/e): 367.03 (MH⁺).

7.3.3165-Fluoro-N4-(3-hydroxyphenyl)-N2-(3-pyridylmethyl)-2,4-pyrimidinediamine(R945165)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine(50 mg, 0.21 mmol) and 3-pyridylmethylamine (68 mg, 0.63 mmol) gave5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-pyridylmethyl)-2,4-pyrimidinediamine(40 mg, 62%). ¹H NMR (CDCl₃): δ 4.40 (d, J=6.3 Hz, 2H), 5.60 (br, 1H),6.62-6.70 (m, 3H), 7.05 (br, 1H), 7.14 (t, J=8.1 Hz, 1H), 7.30 (dd,J=5.1 and 7.8 Hz, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.80 (d, J=3.3 Hz, 1H),8.49 (d, J=4.5 Hz, 1H), 8.66 (s, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ−169.52; LCMS: ret. time: 9.41 min.; purity: 99.25%; MS (m/e): 312.01(MH⁺).

7.3.3175-Fluoro-N4-(3-hydroxyphenyl)-N2-(2-pyridylmethyl)-2,4-pyrimidinediamine(R945166)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine(50 mg, 0.21 mmol) and 2-pyridylmethylamine (68 mg, 0.63 mmol) gave5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-pyridylmethyl)-2,4-pyrimidinediamine(40 mg, 62%). ¹H NMR (CDCl₃): δ 4.73 (d, J=6.3 Hz, 2H), 5.85 (t, J=6.0Hz, 1H, NH), 6.48 (d, J=6.9 Hz, 1H), 6.61 (dd, J=2.7 and 8.1 Hz, 1H),6.67 (s, 1H), 7.13 (t, J=8.1 Hz, 1H), 7.21 (dd, J=5.1 and 7.5 Hz, 1H),7.49 (d, J=7.5 Hz, 1H), 7.69 (td, J=1.8 and 7.8 Hz, 1H), 7.85 (d, J=3.6Hz, 1H), 8.38 (br, 1H), 8.56 (dd, J=1.2 and 3.9 Hz, 1H); ¹⁹F NMR (282MHz, CDCl₃): δ −170.49; LCMS: ret. time: 10.10 min.; purity: 100%; MS(m/e): 312.08 (MH⁺).

7.3.318N4-(3,5-Dimethoxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926802)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,5-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine with3-hydroxyaniline gaveN4-(3,5-dimethoxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 18.98 min.; purity: 90%; MS (m/e): 357 (MH⁺).

7.3.319N4-(3,5-Dimethoxyphenyl)-N2-(2-ethoxycarbonylindol-7-yl)-5-fluoro-2,4-pyrimidinediamine(R926803)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,5-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine with2-ethoxycarbonyl-7-aminoindole gaveN4-(3,5-dimethoxyphenyl)-N2-(2-ethoxycarbonylindol-7-yl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 24.21 min.; purity: 91%; MS (m/e): 452 (MH⁺).

7.3.320N2-(3,4-Dimethoxyphenyl)-N4-(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926108)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-N4-(4-ethoxyphenyl)-5-fluoro-4-pyrimidineaminewith 3,4-dimethoxyaniline gaveN2-(3,4-dimethoxyphenyl)-N4-(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.89 (d, 1H, J=3 Hz), 7.45 (bd, 2H, J=9 Hz), 7.20 (d,1H, J=2.4 Hz), 6.96-6.77 (m, 5H), 6.63 (bs, 1H), 4.03 (q, 2H, J=7.2 Hz),3.86 (s, 3H), 3.72 (s, 3H), 1.42 (t, 3H, J=7.2 Hz); ¹⁹F NMR (CDCl3):−47473.

7.3.321N4-(4-Ethoxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926146)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-N4-(4-ethoxyphenyl)-5-fluoro-4-pyrimidineaminewith 3-hydroxyaniline gaveN4-(4-ethoxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.79 (d, 1H, J=4.2 Hz), 7.54 (dd, 2H, J=2.4 and 7.2Hz), 7.05-6.97 (m, 3H), 6.87 (dd, 2H, J=2.4 and 4.2 Hz), 6.41 (m, 1H),4.02 (q, 2H, J=6.6 Hz), 1.38 (t, 3H, J=6.9 Hz); ¹⁹F NMR (CD₃OD): −47444;LCMS: ret. time: 21.15 min.; purity: 98%; MS (m/e): 341 (MH⁺).

7.3.322N4-(4-Ethoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926213)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-N4-(4-ethoxyphenyl)-5-fluoro-4-pyrimidineaminewith 3,4-ethylenedioxyaniline gaveN4-(4-ethoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.87 (d, 1H, J=3 Hz), 7.47 (dd, 2H, J=2.4 and 5.1 Hz),7.18 (d, 1H, J=2.4 Hz), 6.91-6.85 (m, 3H), 6.79-6.73 (m, 2H), 6.64 (bs,1H), 4.25 (bs, 4H), 4.05 (q, 2H, J=6.9 Hz), 1.43 (t, 3H, J=7.2 Hz); ¹⁹FNMR (CDCl₃): −47467; LCMS: ret. time: 24.32 min.; purity: 90%; MS (m/e):383 (MH⁺).

7.3.323N4-(3,4-Dimethoxyphenyl)-N2-(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926145)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine with4-ethoxyaniline gaveN4-(3,4-dimethoxyphenyl)-N2-(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.90 (bs, 1H), 7.37 (dd, 2H, J=2.4 and 6.3 Hz), 7.21(d, 1H, J=2.4 Hz), 7.03 (dd, 1H, J=2.4 and 8.1 Hz), 6.86-6.80 (m, 4H),6.65 (bs, 1H), 4.00 (q, 2H, J=7.2 Hz), 3.89 (s, 3H), 3.75 (s, 3H), 1.39(t, 3H, J=6.9 Hz); ¹⁹F NMR (CDCl₃): −47501; LCMS: ret. time: 22.69 min.;purity: 98%; MS (m/e): 385 (MH⁺).

7.3.324N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926147)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine with3-hydroxyaniline gaveN4-(3,4-dimethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.77 (d, 1H, J=3.3 Hz), 7.15 (d, 1H, J=2.4 Hz), 7.05(dd, 1H, J=2.4 and 8.4 Hz), 7.00-6.90 (m, 4H), 6.80 (d, 1H, J=8.1 Hz),6.40 (m, 1H), 4.05 (q, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 1.20 (t, 3H);¹⁹F NMR (CD₃OD): −47223; LCMS: ret. time: 17.94 min.; purity: 99%; MS(m/e): 357 (MH⁺).

7.3.325N2-(3,4-Dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926113)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3,4-dimethoxyaniline gaveN2-(3,4-dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.90 (d, 1H, J=6.6 Hz), 7.59 (bs, 1H), 7.30 (s, 1H),7.20-7.10 (m, 2H), 7.00-6.75 (m, 4H), 6.59 (bd, 1H, J=7.8 Hz), 3.87 (s,3H), 3.84 (s, 3H); ¹⁹F NMR (CDCl₃): −47229; LCMS: ret. time: 17.77 min.;purity: 78%; MS (m/e): 357 (MH⁺).

7.3.326N2-(4-Ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926395)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith ethyl-4-aminophenoxyacetate gaveN2-(4-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.90 (d, 1H, J=5.1 Hz), 7.35 (dd, 2H, J=2.1 and 7.2Hz), 7.13 (t, 1H, J=7.2 Hz), 7.10 9d, 1H, J=6.6 Hz), 6.96 (dd, 2H, J=2.4and 7.2 Hz), 6.67 (m, 1H), 4.72 (s, 2H), 4.25 (q, 2H, J=7.2 Hz), 1.29(t, 3H, J=7.2 Hz); ¹⁹F NMR (CD₃OD): −21885; LCMS: ret. time: 20.18 min.;purity: 92%; MS (m/e): 399 (MH⁺).

7.3.3275-Bromo-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926396)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-N4-(3-hydroxyphenyl)-4-pyrimidineamine withethyl 4-aminophenoxyacetate gave5-bromo-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 21.64 min.; purity: 92%; MS (m/e): 459 (MH⁺).

7.3.328N2-(4-Ethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926211)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-ethoxyaniline were reacted to yieldN2-(4-ethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.88 (bs, 1H), 7.40 (bd, 2H, J=8.7 Hz), 7.27 (bd, 2H,J=6.3 Hz), 6.95 (dd, 1H, J=3 and 9 Hz), 6.86-6.77 (m, 3H), 6.58 (s, 1H),4.28 (bs, 4H), 4.01 (q, 2H, J=6.9 Hz), 1.40 (t, 3H, J=6.9 Hz); LCMS:ret. time: 24.46 min.; purity: 90%; MS (m/e): 383 (MH⁺).

7.3.329N2-(3,4-Dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926212)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3,4-dimethoxyaniline were reacted to yieldN2-(3,4-dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 20.98 min.; purity: 74%; MS (m/e): 399 (MH⁺).

7.3.330N2-(3-Chloro-4-fluorophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926218)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3-chloro-4-fluoroaniline were reacted to yieldN2-(3-chloro-4-fluorophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.75 (bd, 1H), 7.70 (bd, 1H), 7.18 (m, 1H), 7.10 (m,1H), 6.90 (m, 2H), 6.75 (m, 1H), 4.20 (bs, 4H); LCMS: ret. time: 25.04min.; purity: 99%; MS (m/e): 392 (MH⁺).

7.3.331N2-(4-tert-Butylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926219)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-tert-butylaniline were reacted to yieldN2-(4-tert-butylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.85 (d, 1H, J=3.6 Hz), 7.44 (bdd, 2H, J=6.3 Hz),7.35-7.31 (m, 3H), 6.93 (dd, 1H, J=2.7 and 8.7 Hz), 6.83 (d, 1H, J=9Hz), 6.80 (bs, 1H), 4.23 (s, 4H), 1.28 (s, 9H); LCMS: ret. time: 27.67min.; purity: 98%; MS (m/e): 395 (MH⁺).

7.3.332N4-(3,4-Ethylenedioxyphenyl)-N2-(4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine(R926220)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-fluoroaniline were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-N2-(4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.92 (bs, 1H), 7.80 (bs, 1H), 7.60 (bd, 2H), 6.90 (m,2H), 6.80 (bs, 1H), 6.65 (bs, 1H), 4.25 (s, 4H); LCMS: ret. time: 22.87min.; purity: 97%; MS (m/e): 357 (MH⁺).

7.3.333N4-(3,4-Ethylenedioxyphenyl)-N2-(3-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine(R926221)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3-fluoroaniline were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-N2-(3-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.76 (d, 1H, J=5.6 Hz), 7.39 (m, 2H), 7.14 (d, 1H,J=2.4 Hz), 6.94-6.85 (m, 3H), 6.75 (d, 1H, J=9 Hz), 4.21 (s, 4H); LCMS:ret. time: 22.60 min.; purity: 100%; MS (m/e): 357 (MH⁺).

7.3.334N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxyethyl)-2,4-pyrimidinediamine(R926229)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and2-methoxyethylamine were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxyethyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.81 (bs, 1H), 7.33 (d, 1H, J=2.4 Hz), 6.93 (dd, 1H,J=2.4 Hz and 9 Hz), 6.81 (d, 1H, J=9 Hz), 6.53 (s, 1H), 4.25 (bs, 2H),3.54 (bs, 2H), 3.36 (s, 3H); LCMS: ret. time: 18.01 min.; purity: 100%;MS (m/e): 321 (MH⁺).

7.3.335N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(4-methoxybenzyl)-2,4-pyrimidinediamine(R926230)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-methoxybenzylamine were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-methoxybenzyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.81 (d, 1H, J=2.7 Hz), 7.27 (m, 3H), 6.86 (m, 3H),6.52 (s, 1H). 5.14 (s, 1H), 4.46 (d, 2H, J=5.4 Hz), 4.24 (s, 4H), 3.78(s, 3H); LCMS: ret. time: 23.06 min.; purity: 94%; MS (m/e): 383 (MH⁺).

7.3.336N2-(2,2-Difluorobenzodioxol-5-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926386)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and2,2-difluoro-5-aminobenzodioxole were reacted to yieldN2-(2,2-difluorobenzodioxol-5-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 9.39 (s, 1H), 9.24 (s, 1H), 8.06 (d, 1H, J=5.6 Hz),7.87 (d, 1H, J=1.8 Hz), 7.27-7.19 (m, 3H), 7.08 (dd, 1H, J=2.4 and 8.7Hz), 6.80 (d, 1H, J=9 Hz), 4.21 (bs, 4H); ¹⁹F NMR (CDCl₃): −14012 and−46487; LCMS: ret. time: 25.32 min; purity: 100%; MS (m/e): 419 (MH⁺).

7.3.337N2-(2-Ethoxycarbonylindol-5-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926476)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and2-ethoxycarbonyl-5-aminoindole were reacted to yieldN2-(2-ethoxycarbonylindol-5-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.84 (d, 1H, J=5.4 Hz), 7.76 (d, 1H, J=3.6 Hz), 7.50(d, 1H, J=9 Hz), 7.23-7.15 (m, 3H), 7.03 (bd, 1H, J=8.7 Hz), 6.78 (d,1H, J=8.7 Hz), 4.38 (q, 2H, J=7.2 Hz), 4.22 (s, 4H), 1.41 (t, 3H, J=6.9Hz); LCMS: ret. time: 23.58 min; purity: 100%; MS (m/e): 451 (MH⁺).

7.3.338N2-(4-Cyanomethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926480)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-cyanomethyleneoxyaniline were reacted to yieldN2-(4-cyanomethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.87 (d, 1H, J=3.6 Hz), 7.52 (d, 1H, J=8.7 Hz), 7.38(bs, 1H), 7.28 (d, 1H, J=2.4 Hz), 6.96-6.86 (m, 3H), 6.65 (bd, 1H), 4.73(s, 2H), 4.29 (m, 4H); ¹⁹F NMR (CDCl₃): −47416; LCMS: ret. time: 20.49min.; purity: 100%; MS (m/e): 394 (MH⁺).

7.3.339N2-(3-Ethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926482)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine andethyl-3-aminophenoxyacetate were reacted to yieldN2-(3-ethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 10.53 (s, 1H), 8.18 (s, 1H), 7.67 (d, 1H, J=4.8 Hz),7.19-7.02 (m, 5H), 6.86 (d, 1H, 9 Hz), 6.71 (dd, 1H, J=1.8 and 9 Hz),4.51 (s, 2H), 4.25 (m, 6H), 1.29 (t, 3H, J=7.5 Hz); ¹⁹F NMR (CDCl₃):−45640; LCMS: ret. time: 22.71 min.; purity: 99%; MS (m/e): 441 (MH⁺).

7.3.340N2-(3-Ethoxycarbonylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R925745)

In like manner to preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3-ethoxycarbonylaniline gaveN2-(3-ethoxycarbonylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.04 (bs, 1H), 7.94 (bs, 1H), 7.90 (bd, 1H), 7.68 (bd,1H, J=7.5 Hz), 7.35 (t, 1H, J=8.1 Hz), 7.28 (d, 1H, J=2.4 Hz), 7.07 (s,1H), 6.93 (dd, 1H, J=3 and 8.7 Hz), 6.83 (d, 1H, J=9 Hz), 6.64 (bs, 1H),4.36 (q, 2H, J=7.2 Hz), 4.26 9s, 4H), 1.35 (t, 3H, J=7.5 Hz); ¹⁹F NMR(CDCl₃): −47247; LCMS: ret. time: 15.88.; purity: 100%; MS (m/e): 411(MH⁺).

7.3.341N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-hydroxyethyl)-2,4-pyrimidinediamine(R925746)

In like manner to preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and2-hydroxyethylamine gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-hydroxyethyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.7 (bs, 1H), 7.32 (d, 1H, J=2.4 Hz), 7.05 (dd, 1H,J=2.4 and 9 Hz), 6.75 (d, 1H, J=8.9 Hz), 4.21 (s, 4H), 3.67 (t, 2H,J=5.7 Hz), 3.38 (t, 2H, J=5.4 Hz); ¹⁹F NMR (CD₃OD): −48518; LCMD: ret.time: 15.54 min.; purity: 100%; MS (m/e): 307 (MH⁺).

7.3.342N2-(4-Ethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R925747)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine andethyl-4-aminophenoxyacetate gaveN2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.88 (bs, 1H), 7.42 (dd, 2H, J=2.4 and 6.9 Hz), 7.28(d, 1H, J=3 Hz), 6.95-6.81 (m, 4H), 6.59 (s, 1H), 4.59 (s, 4H), 4.28 (q,2H, J=6.2 Hz), 1.30 (t, 3H, J=6.1 Hz); 19F NMR (CDCl3): −47570; LCMS:ret. time: 22.74 min.; purity: 100%; MS (m/e): 441 (MH⁺).

7.3.343N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R940233)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3-chloro-4-hydroxy-5-methylaniline gaveN2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: retn, time: 19.20 min.; purity: 94%; MS (m/e): 360 (M⁺); ¹H NMR(CDCl₃): δ 7.93 (1H, d, J=3.1 Hz), 7.54 (1H, d, J=2.6 Hz), 7.30 (1H, t,J=2.1 Hz), 7.21 (1H, t, J=7.9 Hz), 7.02 (3H, m), 6.78 (1H, s), 6.61 (1H,dd, J=7.9 Hz, J=2.1 Hz), 2.26 (3H, s).

7.3.344N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R940235)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-(3-chloro-4-hydroxy-5-methylphenyl)-4-pyrimidineaminewith 3-hydroxyaniline gaveN4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: retn, time: 18.20 min.; purity: 94%; MS (m/e): 360 (M⁺); 1H NMP(DMSO-d6): δ 9.26 (1H, s), 9.23 (1H, s), 9.16 (1H, s), 8.89 (1H, s),8.14 (1H, d, J=4.5 Hz), 7.66 (1H, d, J=2.1 Hz), 7.60 (1H, d, J=2.1 Hz),7.29 (1H, d, J=8.4 Hz), 7.11 (1H, s), 7.06 (1H, t, J=8.4 Hz), 6.41 (1H,d, J=8.4 Hz), 2.30 (3H, s).

7.3.345N2-(3,4-Dimethoxyphenyl)-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-2,4-pyrimidinediamine(R940250)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-4-pyrimidineaminewith 3,4-dimethoxyaniline gaveN2-(3,4-dimethoxyphenyl)-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-2,4-pyrimidinediamine.LCMS: retn, time: 14.72 min.; purity: 94%; MS (m/e): 484 (MH⁺); ¹H NMR(CDCl₃): δ 7.89 (1H, d, J=3.3 Hz), 7.47 (2H, d, J=9 Hz), 7.22 (1H, d,J=2.2 Hz), 6.93-6.76 (5H, m), 6.64 (1H, d, J=2.2 Hz), 4.01 (2H, t, J=5.6Hz), 3.86 (3H, s), 3.72 (3H, s), 3.71 (4H, m), 2.58-2.44 (6H, m), 1.97(2H, m).

7.3.346N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-2,4-pyrimidinediamine(R940251)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-4-pyrimidineaminewith 2-chloro-4-hydroxy-5-methylaniline gaveN2-(2-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-2,4-pyrimidinediamine.LCMS: retn, time: 15.19 min.; purity: 94%; MS (m/e): 488 (MH⁺); ¹H NMR(CDCl₃): δ 7.89 (1H, d, J=3.3 Hz), 7.52 (1H, d, J=2.5 Hz), 7.44 (2H, d,8.7 Hz), 6.97 (1H, d, J=2.5 Hz), 6.91 (2H, d, 9 Hz), 6.71 (1H, s), 6.64(1H, 2.5 Hz), 4.03 (2H, t, J=6.03 Hz), 3.74 (4H, t, J=4.65 Hz),2.60-2.43 (6H, m), 2.23 (3H, s), 1.49 (2H, m).

7.3.347N4-(3,5-Dimethyl-4-hydroxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R940253)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineaminewith ethyl 3-aminophenoxyacetate gaveN4-(3,5-dimethyl-4-hydroxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: retn, time: 21.79 min.; purity: 91%; MS (m/e): 427 (MH⁺); 1H NMR(DMSO-d6): δ 9.80 (1H, s), 8.30 (1H, s), 8.23 (1H, d, J=4.5 Hz),7.37-7.17 (5H, m), 6.66 (1H, d, J=9 Hz), 4.73 (2H, s), 4.25 (2H, q,J=7.2 Hz), 2.23 (6H, s), 1.29 (3H, t, J=7.0 Hz).

7.3.348N2-(3-tert-Butylphenyl)-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidinediamine(R940266)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidineaminewith 3-tert-butylaniline gaveN2-(3-tert-butylphenyl)-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidinediamine.LCMS: retn, time: 28.17 min.; purity: 96%; MS (m/e): 439 (M⁺), 440(MH⁺); ¹H NMR (DMSO-d6): δ 9.40 (1H, s), 9.19 (1H, s), 8.21 (1H, d,J=3.6 Hz), 7.78 (1H, d, J=8.5 Hz) 7.60 (2H, m), 7.48 (1H, t, J=2 Hz),7.31 (1H, t, J=8.5 Hz), 7.25 (1H, t, J=8.5 Hz), 7.02 (1H, d, J=8.5 Hz),6.70 (1H, dd, J=8.5 and 2 Hz), 4.79 (2H, s), 4.26 (2H, q, J=7.2 Hz),1.33 (9H, s), 1.29 (3H, t, J=7.2 Hz).

7.3.3495-Fluoro-N4-(3-isopropylphenyl)-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamineand5-fluoro-N2-(2-ethoxoxycarbonylbenzofur-5-yl)-N4-(3-isopropylphenyl)-2,4-pyrimidinediamineR940284

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hyroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-isopropylphenyl)-4-pyrimidineamine and ethyl3-aminophenoxyacetate were reacted to give the mixture of5-fluoro-N4-(3-isopropylphenyl)-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamineand5-fluoro-N2-(2-ethoxoxycarbonylbenzofur-5-yl)-N4-(3-isopropylphenyl)-2,4-pyrimidinediamine.(R═CO₂Me). LCMS: retn, time: 25.41 min.; purity: 60.61%; MS (m/e): 411(MH⁺); 1H NMR (DMSO-d6): δ 9.38 (1H, s), 9.29 (1H, s), 8.20 (1H, d,J=3.9 Hz), 7.85 (1H, d, J=9.3 Hz), 7.58 (1H, t, J=1.6 Hz), 7.43-7.33(3H, m), 7.18 (1H, t, J=8.2 Hz), 7.05 (1H, d, J=7.8 Hz), 6.53 (1H, dd,J=8.4 Hz, J=2.1 Hz), 4.72 (2H, s), 3.79 (3H, s), 2.95 (1H, quint, J=7.2Hz), 1.26 (6H, d, J=7.2 Hz) (R=CO₂Et) LCMS: retn, time: 26.99 min.;purity: 39%; MS (m/e): 425 (MH⁺); ¹H NMR (DMSO-d6): δ 9.38 (1H, s), 9.29(1H, s), 8.20 (1H, d, J=3.9 Hz), 7.85 (1H, d, J=9.3 Hz), 7.58 (1H, t,J=1.6 Hz), 7.43-7.33 (3H, m), 7.18 (1H, t, J=8.2 Hz), 7.05 (1H, d, J=7.8Hz), 6.53 (1H, dd, J=8.4 and 2.1 Hz), 4.71 (2H, s), 4.25 (2H, q, J=7.2Hz), 2.95 (1H, quint, J=7.2 Hz), 1.31 (3H, t, J=7.2 Hz), 1.26 (6H, d,J=7.2 Hz).

7.3.350N4-(3-tert-Butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamineR940281

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hyroxyphenyl)-2,4-pyrimidinediamine,N4-(3-tert-butylphenyl)-2-chloro-5-fluoro-4-pyrimidineamine and2-methoxycarbonyl-5-aminobenzofuran were reacted to giveN4-(3-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine.LCMS: retn, time: 26.76 min.; purity: 97%; MS (m/e): 435 (MH⁺); ¹H NMR(DMSO-d6): δ 9.41 (2H, sl), 8.27 (1H, s), 8.21 (1H, d, J 3.9 Hz), 7.98(1H, m), 7.77-7.60 (3H, m), 7.37 (1H, t, J 8.1 Hz), 7.22 (1H, d, J 8.1Hz), 3.98 (3H, s), 1.34 (9H, s).

7.3.3515-fluoro-N4-(3-isopropylphenyl)-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamineR940283

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hyroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-isopropylphenyl)-4-pyrimidineamine and2-methoxycarbonyl-5-aminobenzofuran were reacted to give5-fluoro-N4-(3-isopropylphenyl)-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine.LCMS: retn, time: 26.05 min.; purity: 99%; MS (m/e): 420 (M⁺), 422(MH⁺); ¹H NMR (DMSO-d6): δ 10.00 (1H, s), 9.95 (1H, s), 8.31 (1H, d,J=4.8 Hz), 8.11 (1H, s), 7.74 (3H, m), 7.35 (1H, s), 7.35 (1H, t, J=7.2Hz), 7.12 (1H, d, J=7.2 Hz), 3.99 (3H, s), 2.83 (1H, sept, J=6.9 Hz),1.20 (6H, d, J=6.9 Hz).

7.3.352N2-(1,1-Dihydroisobenzofuran-1-one-6-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926786)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with6-amino-1,1-dihydroisobenzofuran-1-one gaveN2-(1,1-dihydroisobenzofuran-1-one-6-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.20 (s, 1H), 9.85 (s, 1H), 8.22 (d, 1H, J=4.8 Hz),8.10 (d, 1H, J=1.2 Hz), 7.86 (dd, 1H, J=2.4 and 8.7 Hz), 7.54 (d, 1H,J=8.4 Hz), 7.22 (d, 1H, J=2.4 Hz), 7.13 (dd, 1H, J=2.1 and 9 Hz), 6.81(d, 1H, J=8.7 Hz), 5.34 (s, 2H), 4.20 (s, 4H); LCMS: ret. time: 17.40min.; purity: 83%; MS (m/e): 395 (MH⁺).

7.3.353N2-[3-(3-Acetamidophenoxy)propyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926787)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with3-N-acetamidophenoxy-3-propylamine gaveN2-[3-(3-acetamidophenoxy)propyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.45 (bs, 1H), 10.07 (s, 1H), 8.42 (s, 1H), 8.20(s, 1H), 7.37 (d, 1H, J=3 Hz), 7.31 (s, 1H), 7.20-7.05 (m, 3H), 6.83 (d,1H, J=9 Hz), 6.53 (d, 1H, J=6.6 Hz), 4.18 (s, 4H), 3.95 (t, 2H, J=6 Hz),2.48 (m, 2H), 2.07 (s, 3H), 1.96 (t, 3H, J=7.8 Hz); LCMS: ret. time:19.58 min.; purity: 99%; MS (m/e): 454 (MH⁺).

7.3.354N2-[4-(4,5-Dichloro-1H-imidazol-1-yl)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926788)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with4,5-dichloro-1H-imidazoleamine gave N2-[4-(4,5-dichloro-1H-imidazol-1-yl)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.10 (s, 1H), 9.85 (s, 1H), 8.20 (d, 1H, J=4.2 Hz),8.01 (s, 1H), 7.78 (d, 1H, J=8.7 Hz), 7.36 (d, 1H, J=9 Hz), 7.25 (d, 1H,J=3 Hz), 7.14 (dd, 1H, J=2.1 and 9 Hz), 6.85 (d, 1H, J=8.7 Hz); LCMS:ret. time: 23.59 min.; purity: 95%; MS (m/e): 474 (MH⁺).

7.3.355N2-(2,4-Dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926789)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with2,4-dimethoxyaniline gaveN2-(2,4-dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.35 (s, 1H), 8.14 (bd, 1H), 7.38 (d, 1H, J=9 Hz),7.23 (s, 1H), 7.09 (d, 1H, J=8.7 Hz), 6.79 (d, 1H, J=8.7 Hz), 6.66 (d,1H, J=2.4 Hz), 6.49 (dd, 1H, J=2.4 and 9 Hz), 4.22 (s, 4H), 3.77 (s,6H); LCMS: ret. time: 20.93 min.; purity: 98%; MS (m/e): 399 (MH⁺).

7.3.356N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(4-isopropylphenyl)-2,4-pyrimidinediamine(R926790)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with4-isopropylaniline gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-isopropylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.30 (s, 1H), 10.50 (s, 1H), 8.22 (d, 1H, J=5.4Hz). 7.37 (d, 1H, J=8.4 Hz), 7.26 (d, 1H, J=3 Hz), 7.18 (s, 1H), 7.15(s, 1H), 7.06 (dd, 1H, J=3.3 and 8.7 Hz), 6.81 (d, 1H, J=8.7 Hz), 4.23(s, 4H), 2.85 (sept., 1H, J=7.2 Hz), 1.17 (d, 6H, J=6.9 Hz); LCMS: ret.time: 24.91 min.; purity: 95%; MS (m/e): 381 (MH⁺).

7.3.357N2-(3,5-Dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926791)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with3,4-dimethoxyaniline gaveN2-(3,5-dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.08 (s, 1H), 9.99 (s, 1H), 8.19 (m, 1H), 7.21 (d,1H, J=2.4 Hz), 7.14 (dd, 1H, J=2.1 and 8.7 Hz), 6.79 (d, 1H, J=9 Hz),6.72 (s, 1H), 6.20 (d, 1H, J=1.8 Hz), 4.21 (s, 4H); LCMS: ret. time:21.19 min.; purity: 93%; MS (m/e): 399 (MH⁺).

7.3.358N2-(2,5-Dimethyl-4-hydroxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926792)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with2,5-dimethyl-4-hydroxyaniline gaveN2-(2,5-dimethyl-4-hydroxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.69 (d, 1H, J=3.9 Hz), 7.16 (d, 1H, J=2.4 Hz), 7.05(d, 1H, J=2.4 Hz), 7.02 (d, 1H, J=1.2 Hz), 6.66 (s, 1H), 6.63 (s, 1H),6.62 (s, 1H), 4.19 (s, 4H), 2.12 (s, 3H), 2.10 (s, 3H); LCMS: ret. time:19.80 min.; purity: 90%; MS (m/e): 383 (MH⁺).

7.3.359N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(5-methyl-3-phenyl-4-oxazolyl)-2,4-pyrimidinediamine(R926793)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with5-methyl-3-phenyl-4-oxazolylamine gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(5-methyl-3-phenyl-4-oxazolyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.80-7.65 (m, 2H), 7.45 (bd, 1H), 7.20 (m, 1H), 7.00(m, 1H), 6.65 (bd, 1H), 4.20 (s, 4H), 2.35 (s, 3H); LCMS: ret. time:20.61 min.; purity: 78%; MS (m/e): 420 (MH⁺).

7.3.360N4-(3,5-Dimethoxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926795)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,5-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine withethyl-3-aminophenoxyacetate gaveN4-(3,5-dimethoxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 21.02 min.; purity: 84%; MS (m/e): 429 (MH⁺).

7.3.361N4-(3,4-Ethylenedioxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926797)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-dimethoxyphenyl)-5-ethoxycarbonyl-4-pyrimidineaminewith ethyl-3-aminophenoxyacetate gaveN4-(3,4-ethylenedioxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine.LCMS: ret. time: 27.60 min.; purity: 82%; MS (m/e): 495 (MH⁺).

7.3.362N4-(3-Hydroxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926798)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-ethoxycarbonyl-N4-(3-hydroxyphenyl)-4-pyrimidineamine withethyl-3-aminophenoxyacetate gaveN4-(3-hydroxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine.LCMS: ret. time: 24.78 min.; purity: 85%; MS (m/e): 453 (MH⁺).

7.3.3635-Fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine(R926614)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 2-methoxycarbonyl-5-aminobenzofuran gave5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 9.42 (s, 1H), 9.33 (s, 1H), 9.23 (s, 1H), 8.26 (s,1H), 8.09 (d, 1H, J=3.6 Hz), 7.59 (m, 3H), 7.13 (m, 3H), 6.53 (d, 1H,J=7.5 Hz), 3.87 (s, 3H), 3.87 (s, 3H).

7.3.364N2-(2-Ethoxycarbonylindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926615)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 2-ethoxycarbony-5-aminoindole gaveN2-(2-ethoxycarbonylindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.95 (d, 1H), 7.84 (d, 1H, J=3.9 Hz), 7.34 (s, 1H),7.33 (d, 1H, J=1.8 Hz), 7.22-7.19 (m, 2H), 7.11-7.05 (m, 2H), 6.55 (m,1H), 4.62 (s, 2H), 4.38 (q, 1H, J=6.9 Hz), 1.40 9t, 3H, J=7.5 Hz).

7.3.365N2-[4-(4,5-Dichloro-1H-imidazol-1-yl)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926777)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith (4,5-dichloro-1H-imidazol-1-yl)-4-aniline gaveN2-[4-(4,5-dichloro-1H-imidazol-1-yl)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 22.09 min.; purity: 98%; MS (m/e): 431 (MH⁺).

7.3.3665-Fluoro-N4-(3-hydroxyphenyl)-N2-(4-isopropylphenyl)-2,4-pyrimidinediamine(R926778)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 4-isopropylaniline gave5-fluoro-N4-(3-hydroxyphenyl)-N2-(4-isopropylphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 23.08 min.; purity: 99%; MS (m/e): 439 (MH⁺).

7.3.367 5-FluoroN4-(3-hydroxyphenyl)-N2-(5-methyl-4-oxazolyl-2-phenyl)-2,4-pyrimidinediamine(R926779)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 5-methyl-4-oxazolyl-2-phenyl-1-amine gave 5-fluoroN4-(3-hydroxyphenyl)-N2-(5-methyl-4-oxazolylphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 23.08 min.; purity: 99%; MS (m/e): 439 (MH⁺). LCMS:ret. time: 19.17 min.; purity: 81%; MS (m/e): 378 (MH⁺).

7.3.368N2-(3.5-Dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926780)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3.5-dimethoxyaniline gaveN2-(3.5-dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 19.61 min.; purity: 97%; MS (m/e): 357 (MH⁺).

7.3.369N4-(4-tert-Butoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl-2,4-pyrimidinediamine(R926572)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction ofN4-(4-tert-butoxycarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineaminewith methyl 4-aminophenoxyacetate gaveN4-(4-tert-butoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.49 (d, 2H, J=8.7 Hz), 7.40 (d, 2H, J=9.3 Hz), 6.89(d, 2H, J=9.3 Hz), 6.85 (d, 2H, J=8.7 Hz), 4.62 (s, 2H), 4.52 (s, 2H),3.81 (s, 3H), 1.49 (s, 9H); LCMS: ret. time: 24.68 min.; purity: 100%;MS (m/e): 499 (MH⁺).

7.3.3705-Fluoro-N4-(3-isopropoxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine(R926487)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-(3-isopropoxyphenyl)-4-pyrimidinediamineamine with2-methoxycarbonyl-5-aminobenzofuran gave5-fluoro-N4-(3-isopropoxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.09 (d, 1H, J=2.4 Hz), 7.96 (d, 1H, J=3 Hz), 7.52 (s,1H), 7.48 (t, 1H, J=1.8 Hz), 7.40 (dd, 1H, J=6.3 Hz), 7.24 9m, 2H), 7.10(m, 1H), 6.97 (bs, 1H), 6.74 (d, 1H, J=2.4 Hz), 6.68 (dd, 1H, J=2.1 and6.9 Hz), 4.49 (sept., 1H, J=5.7 Hz), 3.98 (s, 3H), 1.30 (d, 6H, J=5.7Hz); LCMS: ret. time: 25.86 min.; purity: 94%; MS (m/e): 437 (MH⁺).

7.3.371N4-(4-tert-Butylphenyl)-N2-(2-ethoxycarbonylindol-5-yl)-5-fluoro-2,4-pyrimidinediamine(R926474)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction ofN4-(tert-butylcarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineaminewith 2-ethoxycarbony-5-aminolindole gaveN4-(4-tert-butylphenyl)-N2-(2-ethoxycarbonylindol-5-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.05 (d, 1H, J=1.8 Hz), 7.85 (d, 1H, J=3.9 Hz), 7.58(d, 2H, J=9 Hz), 7.36-7.10 (m, 4H), 7.03 (s, 1H), 6.95 (bd, 1H), 6.84(dd, 1H, J=7.2 Hz), 4.36 (q, 2H, J=7.2 Hz), 1.40 (t, 3H, J=7.5 Hz), 1.33(s, 9H); LCMS: ret. time: 28.67 min.; purity: 100%; MS (m/e): 449 (MH⁺).

7.3.372N4-(4-tert-Butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine(R926477)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction ofN4-(tert-butylcarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineaminewith 2-methoxycarbonyl-5-aminobenzofuran gaveN4-(4-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.6 (s, 1H), 8.09) d, 1H, J=1.8 Hz), 7.86 (d, 1H,J=3.3 Hz), 7.54-7.36 (m, 6H), 6.90 (m, 1H) 3.97 (s, 3H), 1.36 (s, 9H),¹⁹F NMR (CDCl₃): −47188; LCMS: ret. time: 29.69 min.; purity: 84%; MS(m/e): 393 (M-41).

7.3.373N2-(3,4-Ethylenedioxyphenyl)-N4-(2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine(R926485)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidineamine with2-methoxycarbonyl-5-aminobenzofuran gaveN2-(3,4-ethylenedioxyphenyl)-N4-(2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.07 (s, 1H), 7.76 (s, 1H), 7.44 (m, 3H), 7.13 (m,1H), 6.68 (m, 2H0, 4.18 (s, 4H), 3.95 (s, 3H); LCMS: ret. time: 26.63min.; purity: 100%; MS (m/e): 437 (MH⁺).

7.3.374N4-(3-Ethoxycarbonylmethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926774)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidineaminewith 3,4-ethylenedioxyaniline gaveN4-(3-ethoxycarbonylmethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.92 (d, 1H, J=3.6 Hz), 7.67 (s, 1H), 7.40 (s, 1H),7.28-7.21 (m, 2H), 7.01-6.96 (m, 2H), 6.80 (m, 2H), 6.68 (bd, 1H, 1H),4.61 (s, 2H), 4.25 (m, 6H), 1.25 (t, 3H, J=6.9 Hz); LCMS: ret. time:22.03 min.; purity: 84%; MS (m/e): 441 (MH⁺).

7.3.375N4-(3-Ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926775)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidineaminewith 3-hydroxyaniline gaveN4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 19.50 min.; purity: 84%; MS (m/e): 399 (MH⁺).

7.3.376N4-(4-Aminocarbonylmethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945171)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(4-aminocarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidineamineand 3,4-ethylenedioxyaniline gaveN4-(4-aminocarbonylmethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (acetone-d₆): δ 6 4.24-4.31 (m, 4H), 4.51 (s, 2H), 6.77 (d, J=8.7Hz, 1H), 6.95 (dm, J=8.7 Hz, 1H), 7.06 (d, J=9.3 Hz, 2H), 7.28 (m, 1H),7.71 (d, J=9.0 Hz, 2H), 8.15 (m, 1H); LCMS: 15.23 min, 97.05%; MS (m/e):412.01 (MH⁺).

7.3.377 (R935019):5-Fluoro-N2-(3-hydroxyphenyl)-N4-[di-(4-chlorophenyl)methyl]-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine,3-aminophenol andN-(2-chloro-5-fluoro-pyrimidinyl)-1,1-di(4-chlorophenyl)methylamineproduced5-fluoro-N2-(3-hydroxyphenyl)-N4-[di-(4-chlorophenyl)methyl]-2,4-pyrimidinediamine.LCMS: ret. time: 25.59 min.; purity: 91%; MS (m/e): 421 (MH⁺-Cl).

7.3.378 (R935020):N4-(Fluoren-9-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine,2-chloro-N-(fluoren-9-yl)-5-fluoro-4-pyrimidineamine and 3-aminophenolwere reacted to produceN4-(fluoren-9-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.85 (d, 1H, J=2.9 Hz), 7.74 (d, 2H, J=7.6 Hz), 7.64(d, 2H, J=7.6 Hz), 7.41-7.28 (m, 6H), 7.14-7.05 (m, 2H), 6.56 (d, 1H,J=8.8 Hz), 5.28 (d, 1H, J=8.8 Hz); LCMS: ret. time: 23.27 min.; purity:89%; MS (m/e): 385 (MH⁺).

7.3.379 (R935021):(±)-5-Fluoro-N4-[1-(4-fluorophenyl)ethyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine,3-aminophenol and(+)-N-(2-chloro-5-fluoropyrimidinyl)-1-(4-fluorophenyl)ethylamine werereacted to produce the desired(±)-5-fluoro-N4-[1-(4-fluorophenyl)ethyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. ¹H NMR (CDCl₃): δ 7.79 (d, 1H, J=3.3 Hz), 7.38-7.34(dd, 2H, J=5.2 and 8.5 Hz), 7.14 (t, 1H, J=4.5 Hz), 7.09 (d, 1H, J=8.5Hz), 7.03 (d, 1H, J=8.5 Hz), 6.84 (br s, 1H), 6.84-6.78 (ddd, 1H, J=0.8,2.0, and 8.2 Hz), 6.46-6.42 (ddd, 1H, J=0.8, 2.0 and 8.2 Hz), 5.26(overlapped dq, 1H, J=7.1 and 7.9 Hz), 5.18 (d, 1H, J=7.1 Hz), 1.59 (d,3H, J=7.1 Hz); LCMS: ret. time: 21.52 min.; purity: 92%; MS (m/e): 343(MH⁺).

7.3.380 (R935023):(±)-5-Bromo-N4-[1-(4-fluorophenyl)ethyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine,3-aminophenol and(±)-5-bromo-2-chloro-N4-[1-(4-fluorophenyl)ethyl]-4-pyrimidineamine werereacted to produce(±)-5-bromo-N4-[1-(4-fluorophenyl)ethyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.97 (s, 1H), 7.36-7.31 (m, 2H), 7.17 (s, 1H),7.09-7.01 (m, 4H), 6.82 (dd, 1H, J=2.2 and 8.2 Hz), 6.46 (d, 1H, J=2.2and 8.2 Hz), 5.50 (br d, 1H, J=7.0), 5.27 (overlapped dq, 1H, J=7.1 and7.9 Hz), 1.58 (d, 3H, J=7.0 Hz); LCMS: ret. time: 22.64 min.; purity:94%; MS (m/e): 404 (MH⁺).

7.3.381 (R935025):5-Bromo-N2-(3-hydroxyphenyl)-N4-(N-methyl-2-carbomethoxypyrrol-4-yl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine,3-aminophenol and5-bromo-2-chloro-N—(N-methyl-2-carbomethoxypyrrol-4-yl)-4-pyrimidineaminewere reacted to give5-bromo-N2-(3-hydroxyphenyl)-N4-(N-methyl-5-carbomethoxypyrrol-4-yl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃+CD₃OD): δ 7.92 (s, 1H), 7.58 (d, 1H, J=8.0 Hz), 7.09 (d,1H, J=8.5 Hz), 7.04 (d, 1H, J=8.5 Hz), 6.90 (d, 1H, J=4.5 Hz), 6.81 (d,1H, J=1.8 Hz), 6.5 (m, 1H), 3.82 (s, 3H), 3.75 (s, 3H): LCMS: ret. time:19.73 min.; purity: 90%; MS (m/e): 419 (MH⁺).

7.3.382 (R935029):4-Amino-5-bromo-N2-(3-hydroxyphenyl)-2-pyrimidineamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine,4-amino-5-bromo-2-chloropyrimidine and 3-aminophenol were reacted togive 4-amino-5-bromo-N2-(3-hydroxyphenyl)-2-pyrimidineamine. ¹H NMR(DMSO-d6): δ 10.33 (br s, 1H), 8.27 (s, 1H), 7.14-6.06 (m, 2H), 7.01 (d,1H, J=1.7 Hz), 6.54 (td, 1H, J=1.7 Hz and 7.0 Hz).

7.3.383 R935134:5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

The reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamineand 5-(4-aminophenoxymethyl)-3-phenyl-1,2-4-oxadiazole were reacted inmicrowave at 180° C. for 10-20 minutes at 20 bar. Upon concentration andaddition of 2N HCl provided5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.21 (br s, 1H), 9.91 (br s, 1H), 8.18 (d, 1H,J=5.2 Hz), 8.03-7.99 (m, 2H), 7.61-7.53 (m, 3H), 7.46 (br d, 2H, J=7.9Hz), 7.14-7.01 (m, 5H), 6.54 (app d, 1H, J=7.96 Hz), 5.56 (s, 2H); LCMS:ret. time: 24.61 min.; purity: 100%; MS (m/e): 471 (MH⁺).

7.3.384 R935135:5-Fluoro-N4-(4-isopropoxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine and5-(4-aminophenoxymethyl)-3-phenyl-1,2-4-oxadiazole were reacted toprovide5-fluoro-N4-(4-isopropyloxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineas fine flakes of the solid. ¹H NMR (DMSO-d6): δ 10.21 (br s, 1H), 9.93(br s, 1H), 8.17 (d, 1H, J=5.2 Hz), 8.02-7.98 (m, 2H), 7.60-7.49 (m,5H), 7.42 (app d, 2H, J=7.0 Hz), 7.04 (d, 2H, J=9.4 Hz), 6.89 (app d,2H, J=9.4 Hz), 5.56 (s, 2H), 4.58 (septet, 1H, J=6.4 Hz), 1.23 (app d,6H, J=6.4 Hz); LCMS: ret. time: 26.90 min.; purity: 97%; MS (m/e): 513(MH⁺).

7.3.385 R935136:N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxy)phenyl-4-pyrimidineamine and5-(4-aminophenoxymethyl)-3-phenyl-1,2-4-oxadiazole were reacted provideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineas fine flakes of the solid. ¹H NMR (DMSO-d6): δ 10.18 (br s, 1H), 9.12(br s, 1H), 8.14 (d, 1H, 4.7 Hz), 8.02-7.97 (m, 2H), 7.65-7.52 (m, 3H),7.44 (d, 2H, J=8.8 Hz), 7.25-7.23 (m, 1H), 7.15-7.08 (m, 1H), 7.03 (d,2H, J=8.8 Hz), 6.81 (d, 1H, J=8.8 Hz), 5.56 (s, 2H), 4.24-4.20 (m, 4H);LCMS: ret. time: 26.90 min.; purity: 97%; MS (m/e): 513 (MH⁺).

7.3.386 R935137:5-Fluoro-N4-(2-methoxycarbonylbenzofura-5-yl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(2-methoxycarbonylbenzofura-5-yl)-4-pyrimidineamineand 5-(4-aminophenoxymethyl)-3-phenyl-1,2-4-oxadiazole were reacted toprovide5-fluoro-N4-(2-methoxycarbonylbenzofura-5-yl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.21 (br s, 1H), 9.79 (br s, 1H), 8.19 (d, 1H,J=4.7 Hz), 8.09 (br s, 1H), 7.99 (dd, 2H, J=2.3 and 8.2 Hz), 7.76-7.67(m, 2H), 7.59-7.52 (m, 4H), 7.44 (d, 2H, J=8.8 Hz), 7.02 (d, 2H, J=8.8Hz), 5.55 (s, 2H), 3.85 (s, 3H); LCMS: ret. time: 27.61 min.; purity:92%; MS (m/e): 553 (MH⁺).

7.3.387 R935138:5-Fluoro-N2-(3-hydroxyphenyl)-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamineand 3-aminophenol were reacted to provide5-fluoro-N2-(3-hydroxyphenyl)-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineas fine flakes of the solid. ¹H NMR (DMSO-d6): δ 8.12 (d, 1H, J=4.7 Hz),8.03-7.99 (m, 2H), 7.69 (dd, 2H, J=3.5 and 8.8 Hz), 7.61-7.53 (m, 3H),7.06 (d, 2H, J=9.9 Hz), 6.98 (m, 3H), 6.38 (br s, 1H), 5.58 (s, 2H).LCMS: ret. time: 24.83 min.; purity: 96%; MS (m/e): 471 (MH⁺).

7.3.388 R935139:5-Fluoro-N2-(4-isopropoxyphenyl)-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamineand 4-isopropoxyaniline were reacted to provide5-fluoro-N2-(4-isopropoxyphenyl)-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineas fine flakes of the solid. ¹H NMR (DMSO-d6): δ 10.21 (br s, 1H), 9.78(br s, 1H), 8.13 (d, 1H, J=4.7 Hz), 8.02-7.98 (m 2H), 7.65-7.53 (m, 5H),7.34 (d, 2H, J=7.6 Hz), 7.07 (d, 2H, J=9.3 Hz), 6.86 (d, 2H, J=8.8 Hz),5.59 (s, 2H), 4.54 (sept, 1H, J=5.8 Hz), 1.22 (d, 6H, J=5.8 Hz); LCMS:ret. time: 29.64 min.; purity: 97%; MS (m/e): 513 (MH⁺).

7.3.389 R935140:N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamineand 3,4-ethylenedioxyaniline were reacted to provideN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.31 (br s, 1H), 9.59 (br s, 1H), 8.11 (d, 1H,J=4.7 Hz), 8.03-7.99 (m, 2H), 7.68-7.49 (m, 5H), 7.14-7.08 (m, 1H), 7.06(d, 2H, J=8.8 Hz), 6.90 (d, 1H, J=8.8 Hz), 6.76 (d, 1H, J=8.8 Hz), 5.59(s, 2H), 4.22-4.17 (m, 4H); LCMS: ret. time: 21.35 min.; purity: 95%; MS(m/e): 513 (MH⁺).

7.3.390 R935141:5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and5-(4-aminophenoxymethyl)-3-methyl-1,2-4-oxadiazole were reacted toprovide5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineas fine flakes of the solid. ¹H NMR (DMSO-d6): δ 10.91 (br s, 1H), 9.91(br s, 1H), 8.18 (d, 1H, J=4.7 Hz), 7.43 (d, 2H, J=8.8 Hz), 7.15-7.04(m, 3H), 6.96 (d, 2H, J=8.8 Hz), 6.58 (app d, 1H, J=7.6 Hz), 5.43 (s,2H), 2.34 (s, 3H); LCMS: ret. time: 18.68 min.; purity: 95%; MS (m/e):409 (MH⁺).

7.3.391 R935142:5-Fluoro-N4-(4-isopropoxyphenyl)-N2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine and5-(4-aminophenoxymethyl)-3-methyl-1,2-4-oxadiazole were reacted toprovide5-fluoro-N4-(4-isopropoxyphenyl)-N2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineas fine flakes of the solid. ¹H NMR (DMSO-d6): δ 8.16 (d, 1H, J=5.2 Hz),7.52 (dd, 2H, J=3.5 Hz and 9.3 Hz), 7.40 (d, 2H, J=8.8 Hz), 6.98 (d, 2H,J=8.8 Hz), 6.88 (d, 2H, J=9.3 Hz), 5.44 (s, 2H), 4.58 (sept, 1H, J=5.8Hz), 2.34 (s, 3H), 1.24 (d, 6H, J=5.8 Hz); LCMS: ret. time: 24.47 min.;purity: 93%; MS (m/e): 451 (MH⁺).

7.3.392 R935143:N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxy)phenyl-4-pyrimidineamine and5-(4-aminophenoxymethyl)-3-methyl-1,2-4-oxadiazole were reacted toprovideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineas fine flakes of the solid. ¹H NMR (DMSO-d6): δ 9.12 (br s, 1H), 9.04(br s, 1H), 7.99 (d, 1H, J=3.5 Hz), 7.55 (d, 2H, J=1.7 and 8.8 Hz), 7.30(d, 1H, J=2.9 Hz), 7.17 (td, 1H, J=2.9 and 8.8 Hz), 6.88 (d, 2H, J=8.8Hz), 6.77 (d, 1H, J=8.8 Hz), 5.38 (s, 2H), 4.24-4.20 (m, 4H), 2.34 (s,3H); LCMS: ret. time: 21.34 min.; purity: 97%; MS (m/e): 451 (MH⁺).

7.3.393 R935144:5-Fluoro-N2-(4-isopropoxyphenyl)-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamineand 4-isopropoxyaniline were reacted to provide5-fluoro-N2-(4-isopropoxyphenyl)-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineas fine flakes of the solid. ¹H NMR (DMSO-d6): δ 10.11 (br s, 1H), 9.72(br s, 1H), 8.12 (s, 1H, J=5.3 Hz), 7.61 (dd, 2H, J=8.8 Hz), 7.34 (d,2H, J=7.3 Hz), 7.01 (d, 2H, J=8.8 Hz), 6.84 (d, 2H, J=8.8 Hz), 5.47 (s,2H), 4.54 (septet, 1H, J=5.8 Hz), 2.34 (s, 3H), 1.23 (d, 6H, J=6.4 Hz);LCMS: ret. time: 24.31 min.; purity: 96%; MS (m/e): 451 (MH⁺).

7.3.394 R935145:N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamineand 3,4-ethylenedioxyaniline were reacted to provideN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.81 (br s, 1H), 9.67 (br s, 1H), 8.13 (d, 1H,J=4.7 Hz), 7.63 (dd, 2H, J=4.1 and 8.8 Hz), 7.07 (m, 1H), 7.00 (d, 2H,J=8.8 Hz), 6.89 (d, 1H, J=8.8 Hz), 6.76 (d, 1H, J=8.8 Hz), 5.46 (s, 2H),4.22-4-18 (m, 4H), 2.34 (s, 3H); LCMS: ret. time: 21.54 min.; purity:97%; MS (m/e): 451 (MH⁺).

7.3.395 R935146:5-Fluoro-N2-(2-methoxycarbonylbenzofura-5-yl)-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamineand 2-methoxycarbonyl-5-aminobenzofuran were reacted to provide5-fluoro-N2-(2-methoxycarbonylbenzofura-5-yl)-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 8.14 (d, 1H, J=4.7 Hz), 8.02 (s, 1H), 7.63-7.56 (m,5H), 7.02 (d, 2H, J=8.8 Hz), 5.47 (s, 2H), 3.85 (s, 3H), 2.34 (s, 3H);LCMS: ret. time: 22.46 min.; purity: 97%; MS (m/e): 491 (MH⁺).

7.3.396 R935147:5-Fluoro-N2-(3-hydroxyphenyl)-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamineand 3-hydroxyaniline were reacted to provide5-fluoro-N2-(3-hydroxyphenyl)-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineas fine flakes of the product. ¹H NMR (DMSO-d6): δ 8.11 (d, 1H, J=4.6Hz), 7.66 (d, 2H, J=5.8 Hz), 7.06-6.97 (m, 5H), 6.42-40 (m, 1H), 5.46(s, 2H), 2.35 (s, 3H); LCMS: ret. time: 19.00 min.; purity: 95%; MS(m/e): 409 (MH⁺).

7.3.397 R935148:N2-(3,4-Ethylenedioxyphenyl)-N4-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-2,4-pyrimidinediamine

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-Chloro-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-5-fluoro-2,4-pyrimidine amine and 3,4-ethylenedioxyaniline were reacted to produceN2-(3,4-ethylenedioxyphenyl)-N4-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.31 (s, 1H), 8.97 (s, 1H), 8.03 (d, 1H, J=3.5 Hz),7.70 (d, 2H, J=8.8 Hz), 7.29 (d, 1H, J=2.3 Hz), 7.23 (d, 2H, J=8.8 Hz),6.98 (dd, 1H, J=2.1 and 8.8 Hz), 6.66 (d, 1H, 8.2 Hz); 4.19-4.15 (m,4H), 4.07 (qt, 2H, J=7.0 Hz), 1.48 (s, 6H), 1.10 (t, 3H, J=7.0 Hz);LCMS: ret. time: 24.51 min.; purity: 100%; MS (m/e): 453 (MH⁺).

7.3.398 R935150:N2-[4-[(1-Ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(or it can be prepared similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine),2-chloro-5-fluoro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine and4-[ethoxycarbonyl(dimethyl)methyl]aniline were reacted to produceN2-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.18 (br s, 1H), 9.11 (br s, 1H), 8.01 (d, 1H, J=3.5Hz), 7.56 (d, 2H, J=8.8 Hz), 7.54 (d, 2H, J=8.8 Hz), 7.09 (d, 2H, J=8.8Hz), 6.86 (d, 2H, J=8.8 Hz), 4.56 (sept, 1H, J=5.8 Hz), 4.02 (qt, 2H,J=7.0 Hz), 1.43 (s, 6H), 1.26 (d, 6H, J=7.0 Hz), 1.09 (t, 3H, J=7.0 Hz);LCMS: ret. time: 28.49 min.; purity: 98%; MS (m/e): 453 (MH⁺).

7.3.399 R935179:N2-[4-(2,3-Dihydroxypropoxy)phenyl]-N4-(3,4-ethylenedioxypheny)-5-fluoro-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine and4-(2,3-dihydroxypropoxy)aniline were reacted to produceN2-[4-(2,3-dihydroxypropoxy)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.09 (s, 1H), 8.95 (s, 1H), 7.98 (d, 1H, J=3.5 Hz),7.51 (d, 2H, J=8.8 Hz), 7.32 (d, 1H, J=2.3 Hz), 7.17 (dd, 1H, J=2.3 and8.8 Hz), 6.77 (dd, 3H, J=8.8 Hz), 4.90 (d, 1H, J=5.3 Hz), 4.64 (t, 1H,J=5.8 Hz), 4.23-4.19 (m, 4H), 3.91-3.89 (m, 1H), 3.80-3.73 (m, 2H), 3.41(t, 2H, J=5.3 Hz); LCMS: ret. time: 15.04 min.; purity: 96%; MS (m/e):429 (MH⁺).

7.3.400 R935180:N2-[4-(2,3-Dihydroxypropoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine and4-(2,3-dihydroxypropoxy)aniline were reacted to produceN2-[4-(2,3-dihydroxypropoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.38 (s, 1H), 9.18 (s, 1H), 8.98 (s, 1H), 8.12 (d,1H, J=3.5 Hz), 7.58 (d, 2H, J=8.8 Hz), 7.22 (d, 1H, J=2.3 Hz), 7.12 (dd,2H, J=2.3 and 8.8 Hz), 6.79 (d, 2H, J=8.8 Hz), 6.45 (d, 1H, J=8.8 Hz),4.91 (d, 1H, J=5.3 Hz), 4.65 (t, 1H, J=5.8 Hz), 3.92-3.89 (m, 1H),3.79-3.74 (m, 2H), 3.44 (t, 2H, J=5.3 Hz); LCMS: ret. time: 12.79 min.;purity: 89%; MS (m/e): 387 (MH⁺).

7.3.401 R935175:N2-[4-(2,3-Dihydroxypropoxy)phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-isoproxyphenyl)-4-pyrimidineamine and4-(2,3-dihydroxypropoxy)aniline were reacted to produceN2-[4-(2,3-dihydroxypropoxy)phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine:¹H NMR (DMSO-d6): δ 9.12 (s, 1H), 8.91 (s, 1H), 7.97 (d, 1H, J=3.5 Hz),7.58 (d, 2H, J=8.8 Hz), 7.49 (d, 2H, J=8.8 Hz), 6.85 (d, 2H, J=8.8 Hz),6.76 (d, 2H, J=8.8 Hz); 4.89 (d, 1H, J=4.7 Hz), 4.63 (t, 1H, J=5.2 Hz),4.56 (septet, 1H, J=5.8 Hz), 3.90-3.89 (m, 1H), 3.76-3.73 (m, 2H), 3.41(t, 2H, J=5.3 Hz), 1.25 (d, 6H, J=5.8 Hz); LCMS: ret. time: 17.48 min.;purity: 98%; MS (m/e): 429 (MH⁺).

7.3.402 R935169:N4-[4-[(1-Ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-4-pyrimidineamineand 3-aminophenol were reacted to produceN4-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 7.87 (d, 1H, J=3.5 Hz), 7.56 (d, 2H, J=8.8 Hz), 7.35(d, 2H, J=8.8 Hz), 7.25-7.23 (m, 1H), 7.08 (t, 1H, J=8.2 Hz), 6.91 (d,1H, J=2.3 Hz), 6.83 (d, 1H, J=7.6 Hz), 6.50 (dd, 1H, J=1.7 and 8.2 Hz),4.13 (qt, 2H, J=7.0 Hz), 1.58 (s, 6H), 1.19 (t, 3H, J=7.0 Hz); LCMS:ret. time: 22.97 min.; purity: 98%; MS (m/e): 411 (MH⁺).

7.3.403 R935164:5-Fluoro-N4-(4-isopropoxyphenyl)-N2-[(N-methyl-2-methoxycarbonyl)pyrrol-4-yl]-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine,2-chloro-5-fluoro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine andN-methyl-2-methoxycarbonyl-4-aminopyrrole hydrochloride with addeddiisopropylethylamine were reacted to produce the desired product5-fluoro-N4-(4-isopropoxyphenyl)-N2-[(N-methyl-2-carbomethoxy)pyrrol-4-yl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.87 (br s, 1H), 7.44 (d, 2H, J=8.8 Hz), 7.08 (br s,1H), 6.99-6.85 (m, 3H), 6.70 (d, 1H, J=2.3 Hz), 6.63 (d, 1H, J=1.7 Hz),4.52 (septet, 1H, J=5.8 Hz), 3.80 (s, 3H), 3.79 (s, 3H), 1.34 (d, 6H,J=5.8 Hz); LCMS: ret. time: 23.89 min.; purity: 99%; MS (m/e): 400(MH⁺).

7.3.404 R935165:5-Fluoro-N2-(4-isopropoxyphenyl)-N4-[(N-methyl-2-carbomethoxy)pyrrole-4-yl]-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(N-methyl-2-carbomethoxypyrrol-4-yl)-4-pyrimidineamineand 4-isopropoxyaniline were reacted to produce5-fluoro-N2-(4-isopropoxyphenyl)-N4-[(N-methyl-5-carbomethoxy)pyrrol-4-yl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.84 (d, 1H, J=2.3 Hz), 7.36 (d, 2H, J=8.8 Hz), 7.22(d, 1H, J=1.1 Hz), 6.87 (d, 2H, J=8.8 Hz), 6.84 (s, 1H), 6.77 (d, 1H,J=1.7 Hz), 6.61 (br s, 1H), 4.49 (septet, 1H, J=5.8 Hz), 3.82 (d, 3H),3.81 (s, 3H), 1.33 (d, 6H, J=5.8 Hz); LCMS: ret. time: 23.36 min.;purity: 96%; MS (m/e): 400 (MH⁺).

7.3.405 R935166:N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[(N-methyl-2-methoxycarbonyl)pyrrol-4-yl]-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(N-methyl-2-methoxycarbonylpyrrol-2-yl)-4-pyrimidineamineand 3,4-ethylenedioxyaniline were reacted to produce5-fluoro-N2-(3,4-ethylenedioxyphenyl)-N4-[(N-methyl-2-carbomethoxy)pyrrol-4-yl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.84 (d, 1H, J=3.5 Hz), 7.34 (s, 1H), 7.21 (s, 1H),6.82 (d, 2H, J=8.8 Hz), 6.76 (d, 2H, J=8.8 Hz), 6.58 (s, 1H), 4.27-4.18(m, 4H), 3.90 (s, 3H), 3.81 (s, 3H); LCMS: ret. time: 20.02 min.;purity: 93%; MS (m/e): 400 (MH⁺).

7.3.406 R935167:N4-[4-[(1-Ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[4-[1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-4-pyrimidineamineand 4-isopropoxyaniline were reacted to produceN4-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.29 (s, 1H), 8.95 (s, 1H), 8.02 (d, 1H, J=4.1 Hz),7.68 (d, 2H, J=8.8 Hz), 7.46 (d, 2H, J=8.8 Hz), 7.22 (d, 2H, J=8.8 Hz),6.75 (d, 2H, J=8.8 Hz), 4.48 (septet, 1H, J=5.8 Hz), 4.04 (qt, 2H, J=7.0Hz), 1.47 (s, 6H), 1.22 (d, 6H, J=5.8 Hz), 1.10 (t, 3H, J=7.0 Hz); LCMS:ret. time: 28.11 min.; purity: 99%; MS (m/e): 453 (MH⁺).

7.3.407 R935159:5-Fluoro-N4-(4-isopropoxyphenyl)-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[3-hydroxyphenyl]-pyrimidine-2,4-diamine,2-chloro-5-fluoro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine and methyl4-aminophenoxyacetate were reacted to produce5-fluoro-N4-(4-isopropoxyphenyl)-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.88 (d, 1H, J=3.5 Hz), 7.46 (d, 2H, J=8.8 Hz), 7.42(d, 2H, J=8.8 Hz), 6.88 (d, 2H, J=9.3 Hz), 6.85 (d, 2H, J=9.3 Hz), 6.78(br s, 1H), 6.63 (br d, 1H, J=2.3 Hz), 4.61 (s, 2H), 4.53 (septet, 1H,J=6.4 Hz), 3.81 (s, 3H), 1.35 (d, 6H, J=6.4 Hz); LCMS: ret. time: 23.19min.; purity: 97%; MS (m/e): 427 (MH⁺).

7.3.408 R935157:N4-[4-[(1-Ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[3-hydroxyphenyl]-pyrimidine-2,4-diamine,2-chloro-N4-[4-[1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-4-pyrimidineaminewas reacted with 4-(methoxycarbonylmethyleneoxy)aniline to produceN4-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.92 (s, 1H), 7.55 (d, 2H, J=8.7 Hz), 7.43 (d, 2H,J=9.3 Hz), 7.33 (d, 2H, J=8.7 Hz), 6.87 (d, 2H, J=9.3 Hz), 6.79 (s, 1H),6.73 (d, 1H, J=2.3 Hz), 4.62 (s, 2H), 4.13 (qt, 2H, J=7.0 Hz), 3.81 (s,3H), 1.59 (s, 6H), 1.20 (t, 3H, 7.0 Hz); LCMS: ret. time: 25.20 min.;purity: 97%; MS (m/e): 483 (MH⁺).

7.3.409 R935152:N2-[4-[(1-Ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN2-[4-(1-ethoxycarbonyl-1-methyl)ethyl)phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and4-[1-ethoxycarbonyl-1-methyl)ethyl]aniline were reacted to giveN2-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.89 (d, 1H, J=2.9 Hz), 7.24-7.10 (m, 5H), 6.93 (d,1H, J=7.6 Hz), 6.68 (d, 2H, J=8.2 Hz), 4.08 (qt, 2H, J=7.0 Hz), 1.52 (s,3H), 1.49 (s, 3H), 1.16 (t, 3H, J=7.0 Hz); LCMS: ret. time: 22.15 min.;purity: 96%; MS (m/e): 411 (MH⁺).

7.3.410N2-(3-tert-Butylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R940257)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3-tert-buthylaniline gaveN2-(3-tert-butylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 23.82 min.; purity: 100%; MS (m/e): 353 (MH⁺); ¹H NMR(CDCl₃): δ 7.96 (1H, d, J=3 Hz), 7.61 (1H, ddd, J=7.5, 2.2 and 0.9 Hz),7.49 (1H, t, J=2.5 Hz), 7.27 (1H, m), 7.18 (1H, t, J=8.1 Hz), 7.99 (1H,m), 6.94 (1H, s), 6.91 (1H, dd, J=7.5 and 2.5 Hz), 6.80 (1H, d, J=7.5Hz), 6.72 (2H, m), 6.58 (1H, ddd, J=7.5, 2.5 and 0.9 Hz), 6.52 (1H, ddd,J=7.5, 2.5 and 0.9 Hz), 1.28 (9H, s).

7.3.411N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineandN4-(3-chloro-4-hydroxy-5-methylphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R940258)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-(3-chloro-4-hydroxy-5-methylphenyl)-4-pyrimidineaminewith ethyl 3-aminophenoxyacetate gave a mixture ofN4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineandN4-(3-chloro-4-hydroxy-5-methylphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 20.34 min. (CO₂Me); purity: 17%; MS (m/e): 432 (M⁺);LCMS: ret. time: 21.83 min; purity 78%; MS (m/e): 446 (M⁺).

7.3.412N2-(3-tert-Butylphenyl)-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R940260)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-(3,4-dimethoxyphenyl)-4-pyrimidineamine with ethyl3-tert-buthylaniline gaveN2-(3-tert-butylphenyl)-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 24.87 min.; purity: 99%; MS (m/e): 397 (MH⁺); ¹H NMR(CDCl₃): δ 7.92 (1H, d, J=3.4 Hz), 7.50 (1H, d, J=8 Hz), 7.28 (1H, t,J=2.3 Hz), 7.21 (1H, d, J=8 Hz), 718 (1H, m), 7.08-7.01 (2H, m), 6.99(1H, s), 6.84 (2H, d, J=9.2 Hz), 6.65 (1H, s), 3.89 (3H, s), 3.72 (3H,s), 1.26 (9H, s).

7.3.413N2-[2-(N-Benzylpiperazino)ethyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R940261)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 4-(N-benzylpiperazino)ethylamine gaveN2-[2-(N-benzylpiperazino)ethyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 17.15 min.; purity: 90%; MS (m/e): 422 (M⁺), 423 (MH⁺);¹H NMR (CDCl₃): δ 8.42 (1H, s), 7.82 (1H, d, J=3.9 Hz), 7.32-7.08 (6H,m), 6.73 (1H, s), 6.61 (1H, dd, J=8.1 and 2.1 Hz), 6.51 (1H, d, J=7.5Hz), 5.18 (1H, s), 3.59 (2H, m), 3.02 (2H, m), 2.71-2.41 (3H, m),2.10-1.16 (5H, m).

7.3.414N2-[2-(N-Benzylpiperazino)ethyl]-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R940262)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-(3,4-dimethoxyphenyl)-4-pyrimidineamine with4-(N-benzylpiperazino)ethylamine gaveN2-[2-(N-benzylpiperazino)ethyl]-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 17.48 min.; purity: 99%; MS (m/e): 466 (M⁺), 467 (MH⁺);¹H NMR (CDCl₃): δ 7.82 (1H, d, J=3.9 Hz), 7.44 (1H, s), 7.33-7.10 (6H,m), 7.04 (1H, dd, J=8.9 and 2.5 Hz), 6.84 (1H, d, J=8.9 Hz), 6.58 (1H,s), 5.40 (1H, s), 3.91 (3H, s), 3.87 (3H, s), 3.41 (2H, m), 2.87 (2H,m), 2.51 (3H, m), 1.80 (2H, m), 1.60 (4H, m), 1.30 (1H, m).

7.3.415N2-[4-(N-Benzylpiperidino)]-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R940263)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-(3,4-dimethoxyphenyl)-4-pyrimidineamine withN-benzyl-4-aminopiperidine gaveN2-[4-(N-benzylpiperidino)]-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 15.52 min.; purity: 99%; MS (m/e): 438 (MH⁺); ¹H NMR(CDCl₃): δ 7.81 (1H, d, 3.3 Hz), 7.35-7.18 (5H, m), 7.10 (1H, dd, J=8.7and 2.6 Hz), 6.84 (1H, d, J=8.7 Hz), 6.56 (1H, s), 4.73 (1H, d, J=6.9Hz), 3.89 (6H, s), 3.75 (1H, m), 3.51 (2H, m), 2.81 (2H, m), 2.15 (2H,m), 2.00 (2H, m), 1.66-1.44 (4H, m).

7.3.416N2-[4-(N-Benzylpiperidino)]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R940264)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith N-benzyl-4-aminopiperidine gaveN2-[4-(N-benzylpiperidino)]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 14.00 min.; purity: 96%; MS (m/e): 394 (M⁺), 395 (MH⁺);¹H NMR (CDCl₃): δ 7.81 (1H, d, J=3.6 Hz), 7.40-7.28 (5H, m), 7.21-7.14(2H, m), 6.69 (1H, m), 6.62 (1H, m), 6.59 (1H, m), 5.20 (1H, s), 3.65(2H, s), 3.50 (1H, s), 3.03 (1H, m), 2.83 (1H, m), 2.13 (1H, m),1.95-1.70 (1H, m), 1.58 (4H, m).

7.3.417N4-(3-tert-Butylphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R940270)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction ofN4-(3-tert-butylphenyl)-2-chloro-5-fluoro-4-pyrimidineamine with ethyl3-aminophenoxyacetate gaveN4-(3-tert-butylphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 27.30 min.; purity: 98%; MS (m/e): 439 (MH⁺); ¹H NMR(DMSO-d6): δ 9.50 (1H, s), 9.33 (1H, s), 8.11 (1H, dd, J=4.2 and 1.8Hz), 7.81 (1H, d, J=7.2 Hz), 7.49 (1H, t, 2.4 Hz), 7.30-7.28 (3H, m),7.14-7.03 (2H, m), 6.46 (1H, d, J=7.8 Hz), 4.57 (2H, s), 4.13 (2H, q,J=7.2 Hz), 1.23 (9H, s), 1.18 (3H, t, J=7.2 Hz).

7.3.418N4-(3-tert-Butylphenyl)-N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine(R940271)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction ofN4-(3-tert-butylphenyl)-2-chloro-5-fluoro-4-pyrimidineamine with3-chloro-4-hydroxy-5-methylaniline gaveN4-(3-tert-butylphenyl)-N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 25.46 min.; purity: 100%; MS (m/e): 400 (M⁺); ¹H NMR(DMSO-d6): δ 9.63 (1H, s), 9.30 (1H, s), 8.82 (1H, s), 8.20 (1H, d,J=3.9 Hz), 7.92 (1H, d, J=8.8 Hz), 7.58 (2H, m), 7.40-7.20 (3H, m) 2.22(3H, s), 1.35 (9H, s).

7.3.419N2-(3-tert-Butylcarbonylaminophenyl)-N4-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R940275)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3-butylcarbonylaminoaniline gaveN2-(3-tert-butylcarbonylaminophenyl)-N4-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 20.19 min.; purity: 91%; MS (m/e): 396 (MH⁺); ¹H NMR(DMSO-d6): δ 9.42 (1H, s), 9.28 (1H, s), 9.21 (1H, s), 9.18 (1H, s),8.17 (1H, d, J=3.9 Hz), 7.90 (1H, s), 7.55 (1H, dt, J=6.9 and 2.1 Hz),7.51 (1H, dd, J=7.8 and 1.5 Hz), 7.26-7.13 (4H, m), 6.57 (1H, dd, J=7.5and 1.5 Hz), 1.30 (9H, s).

7.3.420N4-(3,3-Dihydroisobenzofuranyl-1-one-6-yl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamineR940294

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hyroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,3-dihydroisobenzofuranyl-1-one-6-yl)-5-fluoro-4-pyrimidineamineand 2-methoxycarbonyl-5-aminobenzofuran were reacted to giveN4-(3,3-dihydroisobenzofuranyl-1-one-6-yl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine.LCMS: ret. time: 21.34 min.; purity: 97%; MS (m/e): 434 (M⁺); ¹H NMR(DMSO-d6): δ 9.90 (1H, s), 9.61 (1H, s), 8.4-8.12 (4H, m), 7.35-7.67(4H, m), 5.50 (2H, s), 3.98 (3H, s).

7.3.421N2-[3-Ethoxycarbonylmethyleneoxyphenyl]-N4-(3,3-dihydroisobenzofuranyl-1-one-6-yl)-5-fluoro-2,4-pyrimidinediamineR940285

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hyroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,3-dihydroisobenzofuranyl-1-one-6-yl)-5-fluoro-4-pyrimidineamineand ethyl 3-aminophenoxyacetate were reacted to giveN2-(3-ethoxycarbonylmethyleneoxyphenyl)-N4-(3,3-dihydroisobenzofuranyl-1-one-6-yl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 20.55 min.; purity: 76%; MS (m/e): 438 (M⁺), 440 (MH⁺);¹H NMR (DMSO-d6): δ 9.70 (1H, s), 9.30 (1H, s), 8.23-8.06 (1H, m), 8.05(1H, s), 7.63 (1H, d, J=8.1 Hz), 7.30 (1H, s), 7.22 (1H, m), 7.08 (1H,t, J=8.1 Hz), 6.43 (1H, d, J=8.1 Hz), 5.37 (1H, s), 5.37 (2H, s), 4.60(2H, s), 4.13 (2H, q, J=7.2 Hz), 1.18 (3H, t, J=7.2 Hz).

7.3.422N2-(3,5-Dimethoxyphenyl)-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926804)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidineaminewith 3,5-dimethoxyaniline gaveN2-(3,5-dimethoxyphenyl)-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 24.12 min.; purity: 86%; MS (m/e): 443 (MH⁺).

7.3.423N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-trifluoromethylphenyl)]-2,4-pyrimidinediamine(R926805)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with3-trifluoromethylaniline gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-trifluoromethylphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 25.88 min.; purity: 89%; MS (m/e): 407 (MH⁺).

7.3.424N2-(2-Ethoxycarbonylindol-7-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine(R926808)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with2-ethoxycarbonyl-7-aminoindole gaveN2-(2-ethoxycarbonylindol-7-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine.LCMS: ret. time: 24.11 min.; purity: 88%, MS (m/e): 450 (MH⁺).

7.3.425N4-[4-(4,5-Dichloro-1H-imidazol-1-yl)phenyl]-5-fluoro-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R926809)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reactionofN-4-[4-(4,5-dichloro-1H-imidazol-1-yl)phenyl]-2-chloro-5-fluoro-4-pyrimidineaminewith ethyl-3-aminophenoxyacetate gave N4-[4-(4,5-dichloro-1H-imidazol-1-ylphenyl)]-5-fluoro-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 25.22 min, purity: 77%; MS (m/e): 519 (MH⁺).

7.3.426N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine(R926813)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with3-(1,3-oxazol-5-yl)aniline gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 20.25 min.; purity: 81%, MS (m/e): 406 (MH⁺).

7.3.427N2-(2-Ethoxycarbonylindol-7-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyridinediamine(R926814)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 2-ethoxycarbonyl-7-aminoindol gaveN2-(2-ethoxycarbonylindol-7-yl)-5-fluoroN4-(3-hydroxyphenyl)-2,4-pyridinediamine. LCMS: ret. time: 25.94 min.;purity: 91%.

7.3.428N2-(3-Aminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950207)

N4-(3,4-Ethylenedioxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine (50 mg,0.18 mmol) was dissolved in dry MeOH (1 ml), to it was added3-aminoaniline (163 mg, 1.2 mmol) and the mixture was refluxed for 4days (70° C. oil-bath temperature). The mixture was cooled to 22° C.,concentrated to dryness under reduced pressure and subjected to columnchromatography on silica gel (CHCl₃-Acetone, 9:1) to giveN2-(3-aminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.66 (d, 1H, J=3.6 Hz), 7.18 (d, 1H, J=2.1 Hz), 7.09(t, 1H, J=2.1 Hz), 6.80-6.90, (m, 1H), 6.69 (d, 1H, J=8.1 Hz), 6.57 (m,1H), 6.20 (m, 1H), 6.60 (m, 1H), 4.10 (m, 4H); LCMS purity: 90.7%; MS(m/e): 354.13 (M⁺, 100).

7.3.429N4-(3,4-Ethylenedioxyphenyl)-N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine(R950186)

In like manner to the preparation ofN2-(3-aminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine and3-ethoxycarbonylmethyleneaminophenylaniline were reacted to prepareN4-(3,4-ethylenedioxyphenyl)-N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 23.29 min.; purity: 95.7%; MS (m/e): 440.41 (MH⁺).

7.3.430N4-(3,5-Dichloro-4-hydroxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950185)

In like manner to the preparation ofN2-(3-aminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(3,5-dichlorophenyl-4-hydroxy)-5-fluoro-4-pyrimidineamineand ethyl 3-aminophenoxyacetate were reacted to prepareN4-(3,5-dichloro-4-hydroxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 22.51 min.; purity: 96.1%; MS (m/e): 466.88 (MH⁺).

7.3.431N4-(3-Aminophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofurane-5-yl)-2,4-pyrimidinediamine(R950162)

A mixture of N4-(3-aminophenyl)-2-chloro-5-fluoro-4-pyrimidineamine (10mg, 0.06 mmol) and 2-methoxycarbonyl-5-aminobenzofuran (36 mg, 0.18mmol) in dry MeOH (0.5 ml) was refluxed for 2 days (100° C. oil-bathtemperature). The mixture was cooled to 22° C., concentrated to drynessunder reduced pressure and subjected to column chromatography on silicagel (CHCl₃:Acetone, 9:1) to giveN4-(3-aminophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofurane-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 8.24 (s, 1H), 7.96 (dd, 1H, J=1.7, 3.5 Hz),7.46-7.59 (m, 3H), 6.93-6.99 (m, 2H), 6.84 (d, 1H, J=8.2 Hz), 6.35 (m,1H), 3.84 (s, 3H); LCMS purity: 97.8%; MS (ES) m/e 394.02 (M⁺, 70).

7.3.432N4-(3-Aminophenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R950163)

In like manner to the preparation ofN4-(3-aminophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofurane-5-yl)-5-fluoro-2,4-pyrimidinediamine,N4-(3-aminophenyl)-2-chloro-5-fluoro-4-pyrimidineamine and3-hydroxyaniline were reacted to prepareN4-(3-aminophenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 7.94 (d, 1H, J=4.1 Hz), 7.20 (m, 2H), 6.89-7.00 (m,4H), 6.30 (m, 2H); LCMS: ret. time: 11.92 min.; purity: 95.0%; MS (m/e):312.09 (MH⁺).

7.3.433N4-(3-Aminophenyl)-5-fluoro-N2-(3-isopropoxyphenyl)-2,4-pyrimidinediamine(R950164)

In like manner to the preparation ofN4-(3-aminophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofurane-5-yl)-5-fluoro-2,4-pyrimidinediamine,N4-(3-aminophenyl)-2-chloro-5-fluoro-4-pyrimidineamine and3-isopropoxyaniline were reacted to prepareN4-(3-aminophenyl)-5-fluoro-N2-(3-isopropoxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 17.52 min.; purity: 98.9%; MS (m/e): 354.13 (MH⁺).

7.3.434N4-(3-Aminophenyl)-5-fluoro-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine(R950165)

In like manner to the preparation ofN4-(3-aminophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofurane-5-yl)-5-fluoro-2,4-pyrimidinediamine,N4-(3-aminophenyl)-2-chloro-5-fluoro-4-pyrimidineamine and4-isopropoxyaniline were reacted to prepareN4-(3-aminophenyl)-5-fluoro-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-D6-MeOD, 300 MHz): δ 7.90 (d, 1H, J=4.1 Hz), 7.47 (m, 2H),7.03 (t, 1H, J=1.7 Hz), 6.60-6.95 (m, 5H), 6.29 (m, 1H), 4.43 (septett,1H, J=6.0 Hz), 1.18 (d, 6H, J=6.0 Hz); LCMS: ret. time: 17.11 min.;purity: 88.4%; MS (m/e): 354.09 (MH⁺).

7.3.435N2-(3-Furylmethylene)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R950210)

In like manner to the preparation ofN4-(3-aminophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofurane-5-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-furylmathylamine were reacted to prepareN2-(3-furylmethylene)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 16.03 min.; purity: 93.5%; MS (m/e): 301.10 (MH⁺).

7.3.4365-Fluoro-N4-(3-hydroxyphenyl)-N2-(4-methoxyphenyloxyethyleneamino)-2,4-pyrimidinediamine(R950211)

In like manner to the preparation ofN4-(3-aminophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofurane-5-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and2-(4-methoxyphenyl)ethylamine were reacted to prepare5-fluoro-N4-(3-hydroxyphenyl)-N2-(4-methoxyphenyloxyethyleneamino)-2,4-pyrimidinediamine.LCMS: ret. time: 18.88 min.; purity: 97.6%; MS (m/e): 371.09 (MH⁺).

7.3.437N4-(3-Aminophenyl)-N2-[[N3-[N4-(3-aminophenyl)]-5-fluoro-2,4-pyrimidinediamine]aminophenyl]-5-fluoro-2,4-pyrimidinediamine(R950137)

2,4-Dichloro-5-fluoropyrimidine and 3-aminoaniline were reacted toprepareN4-(3-aminophenyl)-N2-[[N3-[N4-(3-aminophenyl)]-5-fluoro-2,4-pyrimidinediamine]aminophenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 13.10 min.; purity: 96.4%; MS (m/e): 513.01 (MH⁺).

7.3.438N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(hydroxyethyleneamino)phenyl]-2,4-pyrimidinediamine(R950208)

N2-(3-Aminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand 2-bromoethanol were reacted together to giveN4-(3,4-ethylenedioxyphenyl)-N2-[3-(hydroxyethylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 15.44 min.; purity: 98.6%; MS (m/e): 398.05 (MH⁺).

7.3.439N2-[3-Bis(hydroxyethyl)aminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950209)

N2-(3-Aminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand 2-bromoethanol were reacted together to giveN2-[3-bis(hydroxyethyl)aminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 15.64 min.; purity: 97.8%; MS (m/e): 442.06 (MH⁺).

7.3.4406-Ethoxycarbonyl-N4-(ethoxycarbonylmethyl)-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-5-nitro-2,4-pyrimidinediamine(R925858)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-hydroxyphenyl)-2,4-pyrimidinediamine,N-(2-chloro-6-ethoxycarbonyl-5-nitro-4-pyrimidinyl)glycine ethyl esterand ethyl 4-aminophenoxyacetate were reacted to yield6-ethoxycarbonyl-N4-(ethoxycarbonylmethyl)-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-5-nitro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 9.00 (bs, 1H), 7.49 (bs, 1H), 7.41 (d, 2H, J=9.0 Hz),6.89 (d, 2H, J=9.0 Hz), 4.62 (s, 2H), 4.46 (q, 2H, J=7.2 Hz), 4.31-4.19(m, 6H), 1.40 (t, 3H, J=7.2 Hz), 1.33-1.25 (m, 6H); LCMS: ret. time:30.00 min.; purity: 98%; MS (m/e): 492 (MH⁺).

7.3.441N4-Benzyloxy-5-ethoxycarbonyl-N2-(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine(R925837)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-benzyloxy-2-chloro-5-ethoxycarbonyl-4-pyrimidineamine and1,4-benzodioxan-6-amine were reacted to yieldN4-benzyloxy-5-ethoxycarbonyl-N2-(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 8.55 (s, 1H), 7.49-7.44 (m, 3H), 7.39-7.34 (m, 4H),7.30-7.22 (m, 1H), 6.67 (d, 1H, J=8.4 Hz), 4.98 (s, 2H), 4.23-4.17 (m,6H), 1.26 (t, 3H, J=7.2 Hz); LCMS: ret. time: 26.14 min.; purity: 95%;MS (m/e): 423 (MH⁺).

7.3.442N4-Benzyloxy-5-ethoxycarbonyl-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R925824)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-benzyloxy-2-chloro-5-ethoxycarbonyl-4-pyrimidineamine and3-hydroxyaniline were reacted to yieldN4-benzyloxy-5-ethoxycarbonyl-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 24.28 min.; purity: 88%; MS (m/e): 381 (MH⁺).

7.3.443N2,N4-Bis[4-(aminocarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(R945025)

A mixture of 4-nitrophenol (7.65 g, 55 mmol), 2-bromoacetamide (6.90 g,50 mmol) and K₂CO₃ (13.8 g, 0.1 mol) in acetone (50 mL) was stirred atroom temperature for 24 h. The reaction mixture was diluted with water,and acetone was removed under reduced pressure. The formed light-yellowprecipitate was collected by filtration, washed with water and dried togive 1-aminocarbonylmethyleneoxy-4-nitrobenzene (8.28 g, 84%).

Hydrogenation of 1-aminocarbonylmethyleneoxy-4-nitrobenzene (3 g, 15mmol) in methanol (50 mL) catalyzed by 10% Pd—C(500 mg) and Na₂SO₄ (500mg) at 50 psi for 2 h gave 4-(aminocarbonylmethyleneoxy)aniline (2.59 g,quant.).

4-(Aminocarbonylmethyleneoxy)aniline (500 mg, 3 mmol) and2,4-dichloro-5-fluoropyrimidine (200 mg, 1.2 mmol) were dissolved inmethanol (10 mL) and water (1 mL) and was stirred at 70° C. for 24 h.Then methanol was removed under reduced pressure. The remaining aqueoussolution was acidified with 1 N HCl (80 mL). The formed whiteprecipitate was collected by filtration to giveN2,N4-bis[4-(aminocarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(370 mg, 72%). ¹H NMR (acetone-d₆): δ 4.46 (s, 2H), 4.50 (s, 2H), 6.81(br, NH, 2H), 6.91 (d, J=9.0 Hz, 2H), 6.98 (d, J=9.0 Hz, 2H), 7.20 (br,2H, NH), 7.63 (d, J=9.3 Hz, 2H), 7.72 (d, J=8.7 Hz, 2H), 7.93 (d, J=3.6Hz, 1H), 8.27 (br, 1H, NH), 8.44 (br, 1H, NH); LCMS: ret. time: 13.91min.; purity: 100%; MS (m/e): 427.02 (MH⁺).

7.3.444N2,N4-Bis[4-(cyanomethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(R945032)

To a solution ofN2,N4-bis[4-(aminocarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(200 mg, 0.47 mmol) in THF (10 mL) was added trifluoroacetic anhydride(0.33 mL, 2.35 mmol) and pyridine (0.38 mL, 4.7 mmol) at roomtemperature and was stirred at room temperature overnight. The mixturewas diluted with ethyl acetate (80 mL) and 1 N HCl (80 mL). The organiclayer was washed with 1 N HCl (2×60 mL), water (2×60 mL) and brine (60mL). The ethyl acetate layer was dried and evaporated. The residue wasrecrystallized from ethyl acetate and hexanes to giveN2,N4-bis[4-(cyanomethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(159 mg, 87%) as a white solid. ¹H NMR (acetone-d₆): δ 5.09 (s, 2H),5.16 (s, 2H), 7.08 (d, J=9.3 Hz, 2H), 7.17 (d, J=9.0 Hz, 2H), 7.63 (d,J=9.0 Hz, 2H), 7.77 (d, J=9.3 Hz, 2H), 8.17 (d, J=4.8 Hz, 1H), 9.55 (br,1H, NH), 11.00 (br, 1H, NH); LCMS: 21.47 min.; 96.11%; MS (m/e): 391.20(MH⁺).

7.3.445N2,N4-Bis[4-(1H-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R945033)

To a solution ofN2,N4-bis[4-(cyanomethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(100 mg, 0.26 mmol) in DMF (10 mL) was added NH₄Cl (136 mg, 2.54 mmol),sodium azide (100 mg, 1.54 mmol), and one drop of acetic acid and wasstirred at 70° C. overnight. Then it was titrated with ethyl acetate (80mL) to give precipitation. The precipitate was collected by filtration,washed with 1 N HCl and water to giveN2,N4-bis[4-(1H-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(66 mg, 54%) as a white solid. ¹H NMR (CD₃OD): δ 5.31 (s, 2H), 5.34 (s,2H), 6.93 (d, J=9.0 Hz, 2H), 7.00 (d, J=9.3 Hz, 2H), 7.04 (d, J=9.0 Hz,2H), 7.57 (d, J=9.0 Hz, 2H), 7.81 (d, J=4.2 Hz, 1H); LCMS: 16.54 min.;purity: 88.34%; MS (m/e): 477.02 (MH⁺).

7.3.446N2,N4-Bis(4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R945034)

A mixture of 4-Aminobenzoic acid (410 mg, 3 mmol) and2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) in methanol (10 mL)and water (1 mL) was stirred at 100° C. for 24 h to yieldN2,N4-bis(4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine after methanolwas removal. This residue was redissolved in DMF (10 mL) and to it wasadded potassium carbonate (1.65 g, 12 mmol) and iodomethane (0.37 mL, 6mmol), stirred at room temperature overnight, and then diluted with 1 NHCl (80 mL) and ethyl acetate (80 mL). The ethyl acetate layer waswashed with 1N HCl (60 mL) and water (60 mL). The organic layer wasseparated, dried, evaporated and the resulting residue wasrecrystallized from ethyl acetate/hexanes to giveN2,N4-bis(4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (150mg, 63%). 1H NMR (acetone-d₆): δ 3.85 (s, 3H), 3.88 (s, 3H), 7.88-7.97(m, 4H), 7.98-8.05 (m, 4H), 8.18 (d, J=3.0 Hz, 1H), 9.00 (br, 1H, NH),9.04 (br, 1H, NH); LCMS: ret. time: 27.07 min.; purity: 95.54%; MS(m/e): 397.04 (MH⁺).

7.3.447N2,N4-Bis(3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R945035)

In a manner analogous to the preparation ofN2,N4-bis(4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine, thereaction of 3-aminobenzoic acid (410 mg, 3 mmol) and2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gaveN2,N4-bis(3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (180mg, 76%) as a white solid. ¹H NMR (acetone-d₆): δ 3.81 (s, 3H), 3.83 (s,3H), 7.37 (t, J=8.1 Hz, 1H), 7.47 (t, J=8.1 Hz, 1H), 7.60 (d, J=7.8 Hz,1H), 7.75 (d, J=7.5 Hz, 1H), 8.02 (d, J=6.3 Hz, 1H), 8.10 (d, J=3.6 Hz,1H), 8.24 (d, J=8.4 Hz, 1H), 8.36 (d, J=11.4 Hz, 2H), 8.74 (br, 1H, NH),8.82 (br, 1H, NH); LCMS: ret. time: 22.77 min.; purity: 91.04%; MS(m/e): 397.00 (MH⁺).

7.3.448 N2,N4-Bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945036)

A solution ofN2,N4-bis(3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (100mg, 0.25 mmol) and NaOH (140 mg, 3.5 mmol) in THF:H₂O (5 mL, each) wasstirred at room temperature overnight. The reaction mixture was dilutedwith water (60 mL) and ethyl acetate (60 mL). The aqueous layer wasseparated, acidified with 1N HCl solution to pH 3. The formedprecipitate was collected by filtration and recrystallized from methanolto give N2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine (54mg, 58%) as a white solid. ¹H NMR (CD₃OD): δ 7.31 (t, J=8.1 Hz, 1H),7.42 (t, J=8.1 Hz, 1H), 7.61 (dm, J=7.8 Hz, 1H), 7.76 (dm, J=8.4 Hz,1H), 7.89 (dm, J=7.2 Hz, 1H), 7.98 (d, J=3.6 Hz, 1H), 8.01 (m, 1H), 8.20(m, 1H), 8.37 (m, 1H); LCMS: ret. time: 15.77 min.; purity: 98.84%; MS(m/e): 369.03 (MH⁺).

7.3.449 N2,N4-Bis(4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945037)

In a manner analogous to the preparation ofN2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (100mg, 0.25 mmol) and NaOH (200 mg, 5 mmol) gaveN2,N4-bis(4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine (55 mg, 59%)as a white solid. ¹H NMR (CD₃OD): δ 7.77 (d, J=8.7 Hz, 2H), 7.92 (d,J=8.7 Hz, 2H), 7.94 (d, J=8.4 Hz, 2H), 8.02 (d, J=8.7 Hz, 2H), 8.07 (d,J=3.6 Hz, 1H); LCMS: ret. time: 16.34 min.; purity: 100%; MS (m/e):368.87 (MH⁺).

7.3.450N2,N4-Bis(3-isopropylaminocarbonyloxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926412)

The reaction of 1 equivalent ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine with 3equivalents of isopropyl isocyanate in the presence of pyridine inCH₂Cl₂ at room temperature for 24 h followed by extractive work up usingCH₂Cl₂ gave the desiredN2,N4-bis(3-isopropylaminocarbonyloxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃+CD₃OD): δ 7.82 (d, 1H, J=3.6 Hz), 7.66 (bd, 1H), 7.48 (bd,1H). 7.15-7.02 (m, 2H), 6.76-6.76 (m, 2H), 6.56 (bd, 1H, J=8.1 Hz), 6.45(dd, 1H, J=1.8 and 8.4 Hz), 4.70 (m, 2H), 1.05 (d, 12H, J=6.3 Hz); ¹⁹FNMR (CDCl₃+CD₃OD): −47206; LCMS: ret. time: 15.40 min.; purity: 90%.

7.3.451N2,N4-Bis[4-(ethylaminocarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R945040)

A mixture of 1,4-diaminobenzene (4 g, 37 mmol), ethyl isocyanate (1 mL,12.6 mmol) and potassium carbonate (8.72 g, 63 mmol) in THF (20 mL) wasstirred at room temperature overnight. The reaction mixture waspartitioned in 1N HCl solution (80 mL) and ethyl acetate (80 mL). Theaqueous layer was extracted with ethyl acetate (4×80 mL). The combinedorganic layers was dried, evaporated, recrystallized fromMeOH/CH₂Cl₂/hexanes to give 4-(ethylaminocarbonylamino)aniline (1.4 g,62%) as a beige solid.

In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,4-(ethylaminocarbonylamino)aniline (537 mg, 3 mmol) and2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gaveN2,N4-bis[4-(ethylaminocarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(180 mg, 66%) as a white solid. ¹H NMR (CD₃OD): δ 1.16 (t, J=7.2 Hz,6H), 3.24 (q, J=7.2 Hz, 4H), 7.29 (d, J=9.0 Hz, 2H), 7.40 (t, J=9.0 Hz,4H), 7.55 (d, J=9.0 Hz, 2H), 7.87 (s, 1H, NH), 7.89 (s, 1H, NH); LCMS:ret. time: 16.93 min.; purity: 93.43%; MS (m/e): 453.03 (MH⁺).

7.3.452N2,N4-Bis[3-(ethylaminocarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R945045)

In a manner analogous to the preparation ofN2,N4-bis[4-(ethylaminocarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine,the reaction of 1,3-diaminobenzene (2 g, 18.5 mmol), ethyl isocyanate(0.5 mL, 6.3 mmol) and potassium carbonate (4.36 g, 31.5 mmol) gave3-(ethylaminocarbonylamino)aniline (940 mg, 83%). The reaction of3-(ethylaminocarbonylamino)aniline (537 mg, 3 mmol) and2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gaveN2,N4-bis[3-(ethylaminocarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(180 mg, 66%) as a white solid. ¹H NMR (CD₃OD): δ 1.14 (t, J=6.9 Hz,3H), 1.15 (t, J=7.5 Hz, 3H), 3.21 (q, J=7.2 Hz, 2H), 3.22 (q, J=7.5 Hz,2H), 7.06 (ddd, J=0.9, 2.1, 7.8 Hz, 1H), 7.10-7.28 (m, 5H), 7.53 (t,J=2.1 Hz, 1H), 7.80 (m, 1H), 7.92 (d, J=5.7 Hz, 1H); LCMS: ret. time:17.17 min.; purity: 89.63%; MS (m/e): 453.38 (MH⁺).

7.3.453N2,N4-Bis(4-hydroxy-3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R945043)

A solution ofN2,N4-bis(3-carboxy-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (70mg, 0.17 mmol) and thionyl chloride (0.04 mL, 0.55 mmol) in MeOH (10 mL)was refluxed overnight. Methanol was removed in vacuo. The residue wasdiluted with EtOAc (60 mL) and sodium hydrogen carbonate solution (60mL). The EtOAc layer was washed with NaHCO₃ aqueous solution (60 mL) andwater (60 mL). The organic layer was dried, evaporated and crystallizedfrom MeOH/Et₂O to giveN2,N4-bis(4-hydroxy-3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(58 mg, 77%). ¹H NMR (DMSO-d6): δ 3.69 (s, 3H), 3.71 (s, 3H), 6.81 (d,J=9.3 Hz, 1H), 6.92 (d, J=9.0 Hz, 1H), 7.64 (dd, J=2.7, 9.0 Hz, 1H),7.84 (dd, J=2.1 and 8.4 Hz, 1H), 8.03-8.07 (m, 3H), 9.14 (s, 1H, NH),9.34 (s, 1H, NH), 10.16 (s, 1H, OH), 10.29 (s, 1H, OH); ¹⁹F NMR (282MHz, DMSO-d6): δ −165.60; LCMS: ret. time: 22.24 min.; purity: 100%; MS(m/e): 428.98 (MH⁺).

7.3.454N2,N4-Bis[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R945046)5-Fluoro-N2,N4-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl],[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945047)N2,N4-Bis[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R945048)

CompoundN2,N4-bis[4-(1H-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(30 mg, 0.063 mmol), iodomethane (0.024 mL, 0.38 mmol) and K₂CO₃ (88 mg,0.64 mmol) in DMF (5 mL) was stirred at room temperature overnight. Thenit was diluted with ethyl acetate (50 mL) and water (50 mL). The organiclayer was washed with water (50 mL) and brine (50 mL). After separation,the ethyl acetate layer was dried, evaporated and purified by flashcolumn chromatography (EtOAc/hexanes=2/1, 1/1, EtOAc) to give a mixtureof following compounds:N2,N4-bis[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamineR945046 (6 mg, 19%), ¹H NMR (CDCl₃): δ 4.37 (s, 3H), 4.38 (s, 3H), 5.33(s, 2H), 5.36 (s, 2H), 6.65 (d, J=3.0 Hz, 1H), 6.76 (s, 1H), 6.98 (d,J=9.0 Hz, 2H), 7.04 (d, J=9.3 Hz, 2H), 7.42 (d, J=9.0 Hz, 2H), 7.51 (d,J=9.0 Hz, 2H), 7.90 (br, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ −168.52; LCMS:ret. time: 20.44 min.; purity: 94.92%; MS (m/e): 505.02 (MH⁺);5-fluoro-N2,N4-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl],[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineR945047 (8 mg, 25%), 1H NMR (CDCl₃): δ 4.18 (s, 3H), 4.20 (s, 3H), 4.36(s, 3H), 4.37 (s, 3H), 5.34 (s, 2H), 5.37 (s, 2H), 5.42 (s, 2H), 5.46(s, 2H), 6.69 (br, 2H), 6.80 (s, 1H), 6.83 (s, 1H), 6.91 (d, J=9.3 Hz,2H), 6.98 (d, J=9.0 Hz, 2H), 6.99 (d, J=9.3 Hz, 2H), 7.04 (d, J=9.0 Hz,2H), 7.41 (d, J=9.9 Hz, 2H), 7.44 (d, J=9.3 Hz, 2H), 7.50 (d, J=9.0 Hz,2H), 7.54 (d, J=9.0 Hz, 2H), 7.91 (br, 2H); ¹⁹F NMR (282 MHz, CDCl₃): δ−168.39,−168.16; LCMS: ret. time: 19.42 min.; purity: 91.18%; MS (m/e):504.99 (MH⁺), andN2,N4-bis[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamineR945048 (6 mg, 19%), ¹H NMR (CD₃OD+CDCl₃): δ 4.20 (s, 3H), 4.22 (s, 3H),5.50 (s, 2H), 5.55 (s, 2H), 6.95 (d, J=9.0 Hz, 2H), 7.02 (d, J=9.3 Hz,2H), 7.52 (d, J=9.0 Hz, 2H), 7.66 (d, J=9.3 Hz, 2H), 7.84 (d, J=3.6 Hz,1H); ¹⁹F NMR (282 MHz, CD₃OD+CDCl₃): δ −163.12; LCMS: ret. time: 18.32min.; purity: 83.41%; MS (m/e): 504.99 (MH⁺).

7.3.455N4-(4-Aminocarbonylmethyleneoxyphenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945052)

In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,4-(aminocarbonylmethyleneoxy)aniline (398 mg, 2.4 mmol) and2,4-dichloro-5-fluoropyrimidine (200 mg, 1.2 mmol) gaveN4-(4-aminocarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine(270 mg, 76%). In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof methyl 4-aminophenoxyacetate (183 mg, 1 mmol) andN4-(4-aminocarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine(100 mg, 0.34 mmol) gaveN4-(4-aminocarbonylmethyleneoxyphenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(120 mg, 80%). ¹H NMR (acetone-d₆): δ 3.25 (s, 3H), 3.98 (s, 2H), 4.33(s, 2H), 6.45 (d, J=8.7 Hz, 2H), 6.49 (d, J=9.3 Hz, 2H), 6.93 (d, J=8.7Hz, 2H), 7.13 (d, J=9.0 Hz, 2H), 7.71 (d, J=5.1 Hz, 1H), 9.46 (br, 1H,NH), 9.78 (br, 1H, NH); LCMS: ret. time: 16.65 min.; purity: 100%; MS(m/e): 442.01 (MH⁺).

7.3.456N4-(4-Cyanomethyleneoxyphenyl])5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945053)

In a manner analogous to the preparation ofN2,N4-bis(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine, thereaction ofN4-(4-aminocarbonylmethyleneoxyphenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (80 mg, 0.18 mmol), trifluoroaceticanhydride (0.13 mL, 0.92 mmol) and pyridine (0.15 mL, 1.84 mmol) gaveN4-(4-cyanomethyleneoxyphenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(52 mg, 68%) as a white solid. ¹H NMR (DMSO-d6): δ 3.24 (s, 3H), 4.26(s, 2H), 4.71 (s, 2H), 6.36 (d, J=9.3 Hz, 2H), 6.59 (d, J=9.0 Hz, 2H),7.06 (d, J=9.0 Hz, 2H), 7.28 (d, J=9.0 Hz, 2H), 7.58 (d, J=3.6 Hz, 1H),8.59 (br, 1H, NH), 8.85 (br, 1H, NH); ¹⁹F NMR (282 MHz, DMSO-d6): δ−166.26; LCMS: ret. time: 21.37 min.; purity: 100%; MS (m/e): 424.01(MH⁺).

7.3.457N2,N4-Bis[3-hydroxy-4-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine(R945056)

A solution of 4-amino-2-hydroxybenzoic acid (1 g, 6.5 mmol) in MeOH (15mL) and concentrated sulfonic acid (1 mL) was refluxed overnight. Thereaction mixture was quenched with NaHCO₃ aqueous solution (60 mL) andEtOAc (60 mL). The organic layer was separated, dried, evaporated togive 3-hydroxy-4-methoxycarbonylaniline.

In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,3-hydroxy-4-methoxycarbonylaniline (500 mg, 3 mmol) and2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gaveN2,N4-bis-[3-hydroxy-4-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine(105 mg, 41%). ¹H NMR (DMSO-d6): δ 3.90 (s, 3H), 3.93 (s, 3H), 7.31 (dd,J=2.4, 9.0 Hz, 1H), 7.56 (dd, J=2.1, 8.7 Hz, 1H), 7.63 (d, J=2.1 Hz,1H), 7.67 (d, J=2.1 Hz, 1H), 7.67 (d, J=9.0 Hz, 1H), 7.79 (d, J=9.0 Hz,1H), 8.28 (d, J=3.6 Hz, 1H), 9.72 (s, 1H, NH), 9.82 (s, 1H, NH), 10.77(s, 1H, OH), 10.80 (s, 1H, OH); ¹⁹F NMR (282 MHz, DMSO-d6): δ −161.74;LCMS: ret. time: 31.47 min.; purity: 96.03%; MS (m/e): 428.99 (MH⁺).

7.3.458N2-(4-Aminocarbonylmethyleneoxyphenyl)-5-fluoro-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945060)

In a manner analogous to the preparation ofN4-(4-aminocarbonylmethyleneoxyphenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(4-methoxycarbonylmethyleneoxyphenyl)-4-pyrimidineamine(150 mg, 0.48 mmol) and 4-(aminocarbonylmethyleneoxy)aniline (240 mg,1.44 mmol) gaveN2-(4-aminocarbonylmethyleneoxyphenyl)-5-fluoro-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (145 mg, 68%). ¹H NMR (DMSO-d6): δ 3.70(s, 3H), 4.40 (s, 2H), 4.81 (s, 2H), 6.91 (d, J=8.4 Hz, 2H), 6.93 (d,J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.7 Hz, 2H), 8.21 (d,J=4.8 Hz, 1H), 10.13 (br, 1H, NH), 10.39 (br, 1H, NH); ¹⁹F NMR (282 MHz,DMSO-d6): δ −162.26; LCMS: ret. time: 15.37 min.; purity: 78.49%; MS(m/e): 442.07 (MH⁺).

7.3.459N2,N4-Bis(3-hydroxy-4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945061)

In a manner analogous to the preparation ofN2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionofN2,N4-bis[3-hydroxy-4-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine(70 mg, 0.16 mmol) and NaOH (100 mg, 2.5 mmol) gaveN2,N4-bis(3-hydroxy-4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine (50mg, 77%) as a white solid. 1H NMR (DMSO-d6): δ 7.21 (dd, J=1.5 and 8.7Hz, 1H), 7.46-7.52 (m, 3H), 7.63 (d, J=8.7 Hz, 1H), 7.72 (d, J=8.7 Hz,1H), 8.28 (d, J=3.3 Hz, 1H), 9.71 (s, 1H, NH), 9.79 (s, 1H, NH), 11.34(br, 2H); ¹⁹F NMR (282 MHz, DMSO-d6): δ −161.10; LCMS: ret. time: 20.76min.; purity: 84.65%; MS (m/e): 400.95 (MH⁺).

7.3.460N2-(4-Cyanomethyleneoxyphenyl)-5-fluoro-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945062)

In a manner analogous to the preparation ofN2,N4-bis(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine,N2-(4-aminocarbonylmethyleneoxyphenyl)-5-fluoro-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(100 mg, 0.23 mmol), trifluoroacetic anhydride (0.16 mL, 1.13 mmol) andpyridine (0.18 mL, 2.21 mmol) gaveN2-(4-cyanomethyleneoxyphenyl)-5-fluoro-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(66 mg, 69%) as a white solid. ¹H NMR (acetone-d₆): δ 3.75 (s, 3H), 4.67(s, 2H), 4.89 (s, 2H), 6.88 (d, J=9.0 Hz, 2H), 6.90 (d, J=9.3 Hz, 2H),7.48 (d, J=9.0 Hz, 2H), 7.54 (d, J=9.0 Hz, 2H), 7.84 (d, J=4.2 Hz, 1H),9.17 (br, 1H, NH), 10.59 (br, 1H, NH); ¹⁹F NMR (282 MHz, acetone-d₆): δ−164.65; LCMS: ret. time: 20.69 min.; purity: 94.35%; MS (m/e): 424.02(MH⁺).

7.3.461N2,N4-Bis(3-methoxy-4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R945065)

In a manner analogous to the preparation ofN2,N4-bis[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine,2-methoxy-4-nitrobenzoic acid (1 g, 5 mmol), potassium carbonate (1.4 g,10 mmol) and iodomethane (0.47 mL, 7.5 mmol) gave methyl2-methoxy-4-nitrobenzoate (820 mg, 77%) as a white solid.

The hydrogenation of methyl 2-methoxy-4-nitrobenzoate (700 mg, 3.3 mmol)in methanol (10 mL) catalyzed by 5% Pd—C(100 mg) and Na₂SO₄ (100 mg) at50 psi for 1 h gave methyl 4-amino-2-methoxybenzoate (600 mg, quant.) asa white solid.

In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, methyl4-amino-2-methoxybenzoate (542 mg, 3 mmol) and2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gaveN2,N4-bis(3-methoxy-4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(180 mg, 66%) as a white solid. ¹H NMR (acetone-d₆): δ 3.76 (s, 3H),3.77 (s, 3H), 3.81 (s, 6H), 7.36 (dd, J=1.8, 8.7 Hz, 1H), 7.57 (s, 1H),7.58 (dd, J=2.1 and 7.2 Hz, 1H), 7.69 (d, J=2.1 Hz, 1H), 7.73 (d, J=8.4Hz, 1H), 7.75 (d, J=9.0 Hz, 1H), 8.17 (d, J=3.3 Hz, 1H), 8.89 (s, 2H,NH); ¹⁹F NMR (282 MHz, acetone-d₆): δ −165.18; LCMS: ret. time: 23.17min.; purity: 100%; MS (m/e): 456.96 (MH⁺).

7.3.462N2,N4-Bis(4-methoxy-3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R945066)

In a manner analogous to the preparation ofN2,N4-bis(3-methoxy-4-methoxycarbonyl)phenyl)-5-fluoro-2,4-pyrimidinediamine,2-hydroxy-5-nitrobenzoic acid (1 g, 5.5 mmol), potassium carbonate (3 g,22 mmol) and iodomethane (1 mL, 16 mmol) gave methyl2-hydroxy-5-nitrobenzoate (880 mg, 77%).

The hydrogenation of methyl 2-hydroxy-5-nitrobenzoate (700 mg, 3.3 mmol)using 10% Pd—C(100 mg) and Na₂SO₄ (100 mg) in MeOH at 50 psi gave methyl5-amino-2-methoxybenzoate (600 mg).

In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine, methyl5-amino-2-methoxybenzoate (542 mg, 3 mmol) and2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gaveN2,N4-bis(4-methoxy-3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(170 mg, 62%) as a pink solid. ¹H NMR (acetone-d₆): δ 3.76 (s, 3H), 3.77(s, 3H), 3.88 (s, 3H), 3.93 (s, 3H), 7.08 (dd, J=0.8, 9.0 Hz, 1H), 7.18(d, J=9.0 Hz, 1H), 7.66 (dd, J=3.0 and 8.7 Hz, 1H), 7.78 (dd, J=1.5 and3.0 Hz, 1H), 7.86 (dt, J=2.7 and 9.0 Hz, 1H), 7.98 (t, J=2.7 Hz, 1H),8.32 (d, J=5.1 Hz, 1H); ¹⁹F NMR (282 MHz, acetone-d₆): δ −163.88; LCMS:ret. time: 19.07 min.; purity: 98.17%; MS (m/e): 456.94 (MH⁺).

7.3.463N2,N4-Bis(3-carboxy-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945067)

In a manner analogous to the preparation ofN2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis[4-methoxy-3-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine(80 mg, 0.18 mmol) and NaOH (200 mg, 5 mmol) gaveN2,N4-bis(3-carboxy-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (80mg). ¹H NMR (DMSO-d6): δ 3.75 (s, 3H), 3.80 (s, 3H), 6.94 (d, J=9.6 Hz,1H), 7.05 (d, J=9.3 Hz, 1H), 7.78-7.80 (m, 3H), 7.94 (dd, J=9.3 Hz, 1H),8.04 (d, J=3.6 Hz, 1H), 9.10 (s, 1H, NH), 9.30 (s, 1H, NH); ¹⁹F NMR (282MHz, DMSO-d6): δ −165.56; LCMS: ret. time: 14.65 min.; purity: 100%; MS(m/e): 428.83 (MH⁺).

7.3.464N2,N4-Bis(4-carboxy-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945068)

In a manner analogous to the preparation ofN2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(3-methoxy-4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(30 mg, 0.06 mmol) and NaOH (200 mg, 5 mmol) gaveN2,N4-bis(4-carboxy-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (18mg, 64%) as a white solid. 1H NMR (DMSO-d6): δ 3.66 (s, 3H), 3.73 (s,3H), 7.37 (d, J=8.4 Hz, 1H), 7.47 (s, 1H), 7.49 (s, 1H), 7.61-7.71 (m,3H), 8.25 (d, J=3.6 Hz, 1H), 9.65 (s, 1H, NH), 9.70 (s, 1H, NH); ¹⁹F NMR(282 MHz, DMSO-d6): δ −162.11; LCMS: ret. time: 17.25 min.; purity:100%; MS (m/e): 429.04 (MH⁺).

7.3.465N2-(4-Cyanomethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945070)

In a manner analogous to the preparation ofN2,N4-bis(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine,N2-(4-(aminocarbonylmethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(60 mg, 0.16 mmol), trifluoroacetic anhydride (0.11 mL, 0.8 mmol) andpyridine (0.13 mL, 1.6 mmol) gaveN2-(4-cyanomethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(30 mg, 53%). ¹H NMR (acetone-d₆): δ 5.04 (s, 2H), 6.60 (ddd, J=0.9, 2.4and 8.1 Hz, 1H), 7.02 (d, J=9.3 Hz, 2H), 7.15 (t, J=8.1 Hz, 1H), 7.31(ddd, J=1.2, 2.1 and 8.1 Hz, 1H), 7.38 (t, J=2.1 Hz, 1H), 7.78 (d, J=9.3Hz, 2H), 7.98 (d, J=3.6 Hz, 1H), 8.34 (s, 1H, NH), 8.42 (s, 1H, NH); ¹⁹FNMR (282 MHz, acetone-d₆): δ −168.06; LCMS: ret. time: 18.17 min.;purity: 97.47%; MS (m/e): 352.05 (MH⁺).

7.3.466N4-(4-Cyanomethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945172)

In a manner analogous to the preparation ofN2,N4-bis(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine,N4-(4-aminocarbonylmethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine,trifluoroacetic anhydride and pyridine in THF gaveN4-(4-cyanomethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 4.27 (m, 4H), 4.82 (s, 2H), 6.70 (dd, J=2.4 and 8.4Hz, 1H), 6.75 (d, J=2.4 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 7.02 (d, J=9.0Hz, 2H), 7.32 (d, J=9.0 Hz, 2H), 8.64 (d, J=1.8 Hz, 1H); ¹⁹F NMR (282MHz, CDCl₃): δ −135.58; LCMS: ret. time: 19.92 min.; purity: 98.02%; MS(m/e): 393.98 (MH⁺).

7.3.467N2,N4-Bis[4-[2-methoxyimino(amino)ethyleneoxy]phenyl]-5-fluoro-2,4-pyrimidinediamine(R945096)

N2,N4-Bis(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (50mg, 0.13 mmol), methoxyamine HCl salt (54 mg, 0.65 mmol) and sodiumbicarbonate (54 mg, 0.65 mmol) were dissolved in methanol (5 mL). Thereaction solution was stirred at 70° C. for 7 days. Then methanol wasremoved under reduced pressure. The residue was partitioned in EtOAc (60ml) and water (60 mL). The ethyl acetate layer was washed with water(2×60 mL), dried, evaporated and purified by flash column chromatography(EtOAc/hexanes; 1:1; EtOAc) to giveN2,N4-bis[4-[2-methoxyimino(amino)ethyleneoxy]phenyl]-5-fluoro-2,4-pyrimidinediamine(30 mg, 48%). ¹H NMR (acetone-d₆): δ 3.70 (s, 3H), 3.71 (s, 3H), 4.44(s, 2H), 4.49 (s, 2H), 5.43 (br, 2H), 5.47 (br, 2H), 6.93 (d, J=9.0 Hz,2H), 7.00 (d, J=9.0 Hz, 2H), 7.62 (d, J=9.0 Hz, 2H), 7.71 (d, J=9.0 Hz,2H), 7.93 (d, J=3.6 Hz, 1H), 8.26 (br, 1H, NH), 8.40 (br, 1H, NH); ¹⁹FNMR (282 MHz, acetone-d₆): δ −169.08; LCMS: ret. time: 14.41 min.;purity: 100%; MS (m/e): 484.97 (MH⁺).

7.3.468N2-(4-Carboxymethyleneoxyphenyl)-N4-(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945097)

In a manner analogous to the preparation ofN2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine,N4-(4-cyanomethyleneoxyphenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(10 mg, 0.024 mmol) and LiOH (2 mg, 0.048 mmol) gaveN2-(4-carboxymethyleneoxyphenyl)-N4-(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(5 mg, 52%) as a white solid. 1H NMR (CD₃OD): δ 4.60 (s, 2H), 4.99 (s,2H), 6.88 (d, J=9.0 Hz, 2H), 7.02 (d, J=9.0 Hz, 2H), 7.39 (d, J=8.7 Hz,2H), 7.65 (d, J=9.0 Hz, 2H), 7.84 (d, J=3.9 Hz, 1H); ¹⁹F NMR (282 MHz,CD₃OD): δ −168.81; LCMS: ret. time: 17.95 min.; purity: 86.04%; MS(m/e): 409.99 (MH⁺).

7.3.4695-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945127)

A mixture of 3-nitrophenol (4 g, 29 mmol), bromoacetonitrile (2.5 mL, 36mmol) and K₂CO₃ (8 g, 58 mmol) in acetone (20 mL) was stirred at roomtemperature overnight. The reaction mixture was diluted with water (80mL) and acetone was removed under reduced pressure. The light-yellowprecipitate was collected by filtration, washed with water and dried togive 1-cyanomethyleneoxy-3-nitrobenzene.

1-Cyanomethyleneoxy-3-nitrobenzene (2 g, 11 mmol) was dissolved inmethanol (20 mL) and to the solution was added hydroxyamine HCl salt (1g, 14 mmol) and triethylamine (3 mL, 22 mmol). The reaction mixture wasrefluxed for 2 h and the solvent was removed under reduced pressure. Theresidue was redissolved in THF (30 mL). To the solution was added acetylchloride (4 mL, 56 mmol) and pyridine (9 mL, 0.11 mol). The reactionmixture was stirred at room temperature overnight, then added THF (10mL), water (10 mL) and NaOH (3 g, 75 mmol). The reaction solution wasrefluxed overnight, diluted with water (80 mL). The aqueous solution wasextracted with EtOAc (3×60 mL). After separation, the combined EtOAclayers was dried, evaporated to give1-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxy-3-nitrobenzene.

1-(5-Methyl-1,2,4-oxadiazol-3-yl)methyleneoxy-3-nitrobenzene wasdissolved in THF (10 mL) and water (10 mL) and to it were added sodiumbisulfite (1 g, 5.7 mmol) and sodium bicarbonate (1 g, 12 mmol). Theresulting mixture was stirred at room temperature for 30 min, thendiluted with EtOAc (80 mL) and water (80 mL). The aqueous solution wasextracted with EtOAc (80 mL). The organic layers were combined, dried,evaporated to give 3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyaniline(500 mg, 22% in four steps).

The reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine(40 mg, 0.17 mmol) and3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyaniline (102 mg, 0.50 mmol)gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(35 mg, 51%). ¹H NMR (CDCl₃): δ 2.61 (s, 3H), 5.09 (s, 2H), 6.58-6.62(m, 2H), 6.76 (dt, J=1.2, 8.1 Hz, 1H), 6.84 (dt, J=1.2 and 7.8 Hz, 1H),6.92 (d, J=3.0 Hz, 1H), 7.139 (t, J=8.1 Hz, 1H), 7.145 (t, J=8.1 Hz,1H), 7.25 (m, 1H), 7.54 (dt, J=2.1, 8.7 Hz, 2H), 7.88 (d, J=3.3 Hz, 1H);¹⁹F NMR (282 MHz, CDCl₃): −166.52; LCMS: ret. time: 19.33 min.; purity:84.80%; MS (m/e): 409.35 (MH⁺).

7.3.4705-Fluoro-N2-(3-hydroxyphenyl)-N4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945130)

1-Methoxycarbonylmethyleneoxy-3-nitrobenzene (2 g, 9.5 mmol) wasdissolved in THF (10 mL) and water (10 mL). To the solution was addedNaOH (1 g, 25 mmol). The reaction mixture was stirred at roomtemperature overnight. The solution was diluted with water (60 mL) andEtOAc (60 mL). After extraction, the aqueous layer was separated,acidified with 1N HCl to pH 3. The formed white precipitate wascollected by filtration, washed with water, dried to give1-carboxymethyleneoxy-3-nitrobenzene.

Acetonitrile (2.25 mL, 43 mmol) was dissolved in methanol (10 mL) and tothe solution was added hydroxyamine HCl salt (2 g, 29 mmol) andtriethylamine (8 mL, 57 mmol). The reaction mixture was refluxed for 2days and the solvent was removed under reduced pressure to giveacetamide oxime as white solid.

Acetamide oxime (0.75 g, 10 mmol), 1-carboxymethyleneoxy-3-nitrobenzene(1 g, 5 mmol), EDC HCl (1.45 g, 7.5 mmol) and diisopropylethylamine(2.65 mL, 15 mmol) were dissolved in THF (15 mL) and refluxed for 4 h.The reaction mixture was diluted with EtOAc (60 mL) and water (60 mL).The EtOAc layer was washed with sodium bicarbonate aqueous solution(2×60 mL), 1N HCl (2×60 mL) and water (60 mL). After separation, theEtOAc layer was dried, evaporated to give1-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxy-3-nitrobenzene.

Sodium bisulfite (1.5 g, 8.6 mmol), sodium bicarbonate (1.5 g, 18 mmol)and 1-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxy-3-nitrobenzene (1 g, 4mmol) were dissolved in THF (15 mL) and water (15 mL). It was stirred atroom temperature for 20 min, diluted with EtOAc (60 mL) and water (60mL). The aqueous solution was extracted with EtOAc (2×60 mL). Theorganic layers were combined, dried, evaporated to give3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyaniline.

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyaniline(369 mg, 1.8 mmol) and 2,4-dichloro-5-fluoropyrimidine (150 mg, 0.9mmol) gave2-chloro-5-fluoro-N4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamine.The reaction of2-chloro-5-fluoro-N4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamine(20 mg, 0.06 mmol) and 3-hydroxyaniline (20 mg, 0.18 mmol) gave5-fluoro-N2-(3-hydroxyphenyl)-N4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(10 mg, 42%). ¹H NMR (CDCl₃): δ 2.42 (s, 3H), 5.28 (s, 2H), 6.49 (ddd,J=0.9, 2.7 and 8.4 Hz, 1H), 6.73 (ddd, J=0.9, 2.7 and 8.4 Hz, 1H),6.81-6.84 (m, 2H), 6.88 (ddd, J=0.6, 2.1 and 8.1 Hz, 1H), 7.13 (t, J=8.1Hz, 1H), 7.26 (t, J=8.1 Hz, 1H), 7.40 (br, 1H), 7.49 (t, J=2.1 Hz, 1H),7.94-7.97 (m, 2H); ¹⁹F NMR (282 MHz, CDCl₃): δ −167.11; LCMS: ret. time:18.80 min.; purity: 92.01%; MS (m/e): 409.01 (MH⁺).

7.3.4715-Fluoro-N4-(2-methoxycarbonylbenzofuran-5-yl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945131)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction ofN4-(2-carboxybenzofuran-5-yl)-2-chloro-5-fluoro-4-pyrimidineamine (50mg, 0.16 mmol) and 3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyaniline(100 mg, 0.49 mmol) gaveN4-(2-carboxybenzofuran-5-yl)-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.

In a manner analogous to the preparation ofN2,N4-bis[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine,the reaction ofN4-(2-carboxybenzofuran-5-yl)-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,potassium carbonate (100 mg, 0.7 mmol) and iodomethane (0.03 mL, 0.5mmol) gave5-fluoro-N4-(2-methoxycarbonylbenzofuran-5-yl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(40 mg, 50%). ¹H NMR (acetone-d6): δ 2.63 (s, 3H), 3.94 (s, 3H), 5.04(s, 2H), 6.65 (ddd, J=0.9, 2.4 and 7.8 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H),7.24 (ddd, J=1.2, 1.8 and 8.1 Hz, 1H), 7.58 (d, J=1.2 Hz, 1H), 7.64 (d,J=9.3 Hz, 1H), 7.67 (t, J=2.1 Hz, 1H), 7.88 (dd, J=2.1 and 9.0 Hz, 1H),8.04 (d, J=3.6 Hz, 1H), 8.26 (d, J=1.8 Hz, 1H), 8.47 (br, 1H, NH), 8.71(br, 1H, NH); ¹⁹F NMR (282 MHz, acetone-d₆): δ −167.73; LCMS: ret. time:22.55 min.; purity: 85.43%; MS (m/e): 490.97 (MH⁺).

7.3.472N4-(2-Carboxybenzofuran-5-yl)-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945134)

In a manner analogous to the preparation ofN2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof5-fluoro-N4-(2-methoxycarbonylbenzofuran-5-yl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(20 mg, 0.04 mmol) and NaOH (10 mg, 0.25 mmol) gaveN4-(2-carboxybenzofuran-5-yl)-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (acetone-d₆): δ 2.63 (s, 3H), 5.04 (s, 2H), 6.64 (d, J=8.1 Hz,1H), 7.17 (t, J=8.1 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.56 (s, 1H), 7.62(d, J=9.3 Hz, 1H), 7.67 (t, 1H), 7.86 (dd, J=1.8 and 9.0 Hz, 1H), 8.04(d, J=3.3 Hz, 1H), 8.26 (d, 1H), 8.48 (br, 1H, NH), 8.71 (br, 1H, NH);LCMS: ret. time: 18.00 min.; purity: 75.13%; MS (m/e): 476.70 (MH⁺).

7.3.473N4-(2-Aminocarbonylbenzofuran-5-yl)-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945135)

A mixture of5-fluoro-N4-(2-methoxycarbonylbenzofuran-5-yl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(20 mg, 0.04 mmol) and concentrated NH₄OH (5 mL) in methanol (5 mL) wasstirred at room temperature overnight. The solvent was evaporated togiveN4-[2-(aminocarbonyl)benzofuran-5-yl]-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (acetone-d₆): δ 2.61 (s, 3H), 5.04 (s, 2H), 6.64 (ddd, J=0.9, 2.4and 8.1 Hz, 1H), 7.16 (t, J=8.1 Hz, 1H), 7.27 (ddd, J=0.9, 1.8 and 8.4Hz, 1H), 7.44 (d, J=0.6 Hz, 1H), 7.55 (dd, J=0.6 and 8.1 Hz, 1H), 7.64(t, J=2.4 Hz, 1H), 7.79 (dd, J=2.4 and 9.0 Hz, 1H), 8.03 (d, J=3.6 Hz,1H), 8.24 (d, J=2.4 Hz, 1H), 8.48 (br, 1H, NH), 8.68 (br, 1H, NH); ¹⁹FNMR (282 MHz, acetone-d₆): δ −167.80; LCMS: ret. time: 17.43 min.;purity: 100%; MS (m/e): 475.62 (MH⁺).

7.3.4745-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(2-methoxyimino(amino)ethyleneoxy)phenyl]-2,4-pyrimidinediamine(R945167)

In a manner analogous to the preparation ofN2,N4-bis[4-(2-methoxyimino(amino)ethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine,the reaction ofN2-(4-cyanomethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(50 mg, 0.14 mmol), methoxyamine HCl salt (0.71 mmol) and triethylamine(0.2 mL, 1.4 mmol) gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(2-methoxyimino(amino)ethyleneoxy)phenyl]-2,4-pyrimidinediamine(40 mg, 70%). ¹H NMR (CDCl₃): δ 3.82 (s, 3H), 4.50 (s, 2H), 4.87 (br,2H, NH), 6.60 (ddd, J=0.9, 2.4 and 8.1 Hz, 1H), 6.79-6.84 (m, 2H), 6.86(d, J=8.7 Hz, 2H), 7.00 (s, 1H), 7.14 (t, J=8.1 Hz, 1H), 7.34 (d, J=9.0Hz, 2H), 7.47 (t, J=2.1 Hz, 1H), 7.87 (d, J=3.3 Hz, 1H); ¹⁹F NMR (282MHz, CDCl₃): δ −167.67; LCMS: ret. time: 13.69 min.; purity: 92.51%; MS(m/e): 399.01 (MH⁺).

7.3.475N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[4-methoxyimino(amino)ethyleneoxyphenyl]-2,4-pyrimidinediamine(R945175)

In a manner analogous to the preparation ofN2,N4-bis[4-(2-methoxyimino(amino)ethyleneoxyphenyl)]-5-fluoro-2,4-pyrimidinediamine,N4-(4-cyanomethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine,methoxyamine hydrochloride salt and triethylamine gaveN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-methoxyimino(amino)ethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (acetone-d₆): δ 3.70 (s, 3H), 4.21-4.28 (m, 4H), 4.48 (s, 2H),5.46 (br, 2H), 6.71 (d, J=8.7 Hz, 1H), 6.99 (d, J=9.0 Hz, 2H), 7.06 (dd,J=2.4 and 8.7 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 7.72 (d, J=9.3 Hz, 2H),7.93 (d, J=3.3 Hz, 1H), 8.22 (br, 1H, NH), 8.40 (br, 1H, NH); ¹⁹F NMR(282 MHz, acetone-d₆): δ −169.05; LCMS: ret. time: 16.49 min.; purity:96.47%; MS (m/e): 440.96 (MH⁺).

7.3.476N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926495)

A mixture of N2-(3-ethoxy/ormethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(19.8 g, 45 mmol), methylamine hydrochloride (30.63 g, 450 mmol) anddiisopropylethylamine (78.07 mL, 450 mmol) in MeOH (450 mL) was stirredin a pressure bottle at 100° C. for 8 h (followed by TLC). The reactionwas cooled to room temperature, diluted with H₂O (6 lit), the solidobtained was filtered, washed with H₂O and dried to obtain 18 g ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxyphenyl)]-2,4-pyrimidinediamine.Alternatively, the reaction of equimolar amount of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-aminopyridine with3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in a pressure tubeat 110° C. for 24 h and or in EtOH using microwave at 175° C. for 10-20min followed by aqueous work up gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.90 (s, 1H), 7.89 (bs, 1H), 7.38 (d, 1H, J=2.4 Hz),7.28 (d, 1H, J=2.4 Hz), 7.17-7.09 (m, 2H), 6.79 (d, 1H, J=9 Hz), 6.57(m, 1H), 4.38 (s, 2H), 4.24 (s, 4H), 2.81 (s, 3H); LCMS: ret. time:18.20 min.; purity: 98%; MS (m/e): 426 (MH⁺).

7.3.477N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R921219)

In like manner toN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)-N2-(3-ethoxyocarbonylmethyleneoxyphenyl)-5-fluoro-pyrimidinediamineand methylamine hydrochloride were reacted to yieldN4-(1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.8 (d, 1H), 7.4 (m, 1H), 7.05 (m, 2H), 7.0 (s, 1H),6.8 (dd, 1H), 6.66 (d, 1H), 6.56 (dd, 1H), 4.35 (s, 2H), 4.18 (m, 2H),3.25 (m, 2H), 2.8 (s, 3H); LCMS: ret time: 18.0 min. purity: 97%; MS(m/e): 425 (MH⁺).

7.3.478N4-(3,4-Ethylendioxyphenyl)-5-fluoro-N2-[4-(N-2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R909239)

In like manner toN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand 2-hydroxyethylamine were reacted to yieldN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[4-(N-2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine. ¹H NMR (D₂O): δ 8.02(d, 1H, J=4 Hz), 7.40 (m, 2H), 7.28 (m, 1H), 7.05 (m, 5H), 4.83 (s, 2H),4.5 (m, 2H), 4.23 (m, 2H), 4.03 (m, 2H), 3.87 (m, 2H); LCMS: ret. time:17.17 min.; purity: 94%; MS (m/e): 456 (MH⁺).

7.3.479N4-(3,4-Ethylendioxyphenyl)-5-fluoro-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R909240)

In like manner toN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-(N-methylamino)carbonylmethyleneoxyaniline were reacted to yieldN4-(3,4-ethylendioxyphenyl)-5-fluoro-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (D₂O): δ 8.02 (d, 1H, J=4 Hz), 7.40 (m, 2H), 7.28 (m, 1H), 7.05(m, 5H), 4.83 (s, 2H), 4.5 (m, 2H), 4.23 (m, 2H), 3.87 (s, 3H); LCMS:ret. time: 18.43 min.; purity: 94%; MS (m/e): 426 (MH⁺).

7.3.480N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[3-(N-2-hydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R909251)

In like manner toN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)-N2-(3-ethoxyocarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamineand 2-hydroxypropylamine were reacted to yieldN4-(1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-2-hydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 7.99 (d, 1H, J=4 Hz), 7.25 (m, 2H), 7.04 (m, 1H),6.82 (m, 2H), 6.58 (m, 1H), 6.45 (m, 1H) 4.36 (s, 2H), 4.02 (m, 2H),3.75 (m, 1H), 3.31 (m, 2H), 3.00 (m, 2H), 1.00 (m, 3H); LCMS: ret. time:17.33 min.; purity: 97%; MS (m/e): 469 (MH⁺).

7.3.481N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[3-(N-3-hydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R909252)

In like manner toN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)-N2-[3-ethoxyocarbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamineand 3-hydroxypropylamine were reacted to yieldN4-(1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-3-hydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 7.99 (d, 1H, J=4 Hz), 7.39 (m, 2H), 7.04 (m, 1H),6.87 (m, 2H), 6.55 (m, 1H), 6.41 (m, 1H), 4.29 (s, 2H), 4.02 (m, 2H),3.35 (m, 2H), 3.31 (m, 2H), 3.09 (m, 2H), 1.50 (m, 3H); LCMS: ret. time:17.11 min.; purity: 94%; MS (m/e): 469 (MH⁺).

7.3.482N4-(1,4-Benzoxazin-6-yl)-N2-[3-(N-isopropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R909254)

In like manner toN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)]-N2-(3-ethoxyocarbonylmethyleneoxyphenyl)-5-fluoro-pyrimidinediamineand isopropylamine were reacted to yieldN4-(1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-isopropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 7.79 (d, 1H, J=4 Hz), 7.25 (m, 1H), 7.14 (m, 1H),7.02 (m, 1H), 6.85 (m, 3H), 6.63 (m, 1H), 4.39 (s, 2H), 4.12 (m, 2H),4.05 (m, 1H), 3.38 (m, 2H), 1.20 (m, 6H); LCMS: ret. time: 20.83 min.;purity: 96%; MS (m/e): 453 (MH⁺).

7.3.4835-Fluoro-N4-(4-isopropoxyphenyl)-N2-[2-(N-pyrrolidino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926703)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamineand pyrrolidine were reacted to yield5-fluoro-N4-(4-isopropoxyphenyl)-N2-[2-(N-pyrrolidino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.83 (s, 1H), 7.79 (d, 1H, J=5.4 Hz), 7.42 (bs, 1H),7.39 (d, 2H, J=8.7 Hz), 7.28-7.24 (m, 2H), 6.81 (d, 2H, J=8.7 Hz), 4.52(2q, 1H, J=6.0 Hz), 3.92 (t, 2H, J=6.9 Hz), 3.67 (t, 2H, J=6.9 Hz),2.05-1.90 (m, 4H), 1.32 (d, 6H, J=6.6 Hz); ¹⁹F NMR (CDCl₃): −24000;LCMS: ret. time: 23.49 min.; purity: 97%; MS (m/e): 476 (MH⁺).

7.3.484N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926708)

In a manner similar to the preparation ofN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.10 (bs, 1H), 9.88 (bs, 1H), 8.15 (t, 1H, J=4.5Hz), 8.05 (bs, 1H), 7.40 (d, 2H, J=8.7 Hz), 7.23 (d, 1H, J=2.1 Hz), 7.11(dd, 1H, J=2.4 and 8.7 Hz), 6.89 (d, 2H, J=8.7 Hz), 6.81 (d, 1H, J=8.7Hz), 4.42 (s, 2H), 4.23 (s, 4H), 2.64 (d, 3H, J=4.5 Hz); LCMS: ret.time: 17.60 min.; purity: 96%; MS (m/e): 426 (MH⁺).

7.3.485N4-(4-tert-Butylphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926494)

In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(4-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediaminewith methylamine hydrochloride gaveN4-(4-tert-butylphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.04 (d, 1H, J=2.4 Hz), 7.88 (d, 1H, 4.2 Hz),7.58-7.30 (m, 7H), 2.94 (s, 3H), 1.33 (s, 9H); LCMS: ret. time: 22.86min.; purity: 94%; MS (m/e): 434 (MH⁺).

7.3.486N4-(4-tert-Butylphenyl)-5-fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926712)

In a manner similar to the preparation ofN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-[4-(tert-butyl)phenyl]-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yieldN4-(4-tert-butylphenyl)-5-fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.92 (d, 1H, J=5.4 Hz), 7.53 (d, 2H, J=8.7 Hz), 7.40(d, 2H, J=8.7 Hz), 7.34 (d, 2H, J=8.7 Hz), 7.03 (d, 2H, J=8.7 Hz), 4.52(s, 2H), 2.82 (s, 3H), 1.35 (s, 9H); ¹⁹F NMR (CD₃OD): −46174; LCMS: ret.time: 23.34 min.; purity: 94%; MS (m/e): 424 (MH⁺).

7.3.487N4-(3-tert-Buthylpheny)-5-fluoro-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineR940295

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3-tert-butylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand 2-hydroxyethylamine were reacted to giveN4-(3-tert-butylpheny)-5-fluoro-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 21.34 min.; purity: 97%; MS (m/e): 453 (M⁺); 454 (MH⁺);¹H NMR (CDCl₃): δ 10.34 (1H, s), 7.76 (1H, m), 7.52 (1H, m), 7.4-7.1(5H, m), 6.98 (1H, m), 6.7 (1H, m), 4.36 (2H, s), 3.77 (2H, t, J 5 Hz),3.51 (2H, m), 1.27 (9H, s).

7.3.488N2,N4-Bis[4-(N-pyrrolidino)carbonylmethyleneoxyphenyl]-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926562)

In like manner of the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediaminewith pyrrolidine gaveN2,N4-bis[4-(N-pyrrolidino)carbonylmethyleneoxyphenyl]-5-ethoxycarbonyl-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.17 (s, 1H), 8.73 (bs, 1H), 7.50 (bd, 2H, J=9.0Hz), 7.43 (d, 2H, J=2.4 and 6.9 Hz), 6.91 (m, 4H), 4.64 (s, 2H), 4.62(s, 2H), 4.34 (q, 2H, J=7.2 Hz), 3.53 (m, 8H), 1.95 (m, 4H), 1.86 (m,4H), 1.38 (t, 3H, J=6.9 Hz); LCMS: ret. time: 22.54 min.; purity: 100%;MS (m/e): 590 (MH⁺).

7.3.489N2,N4-Bis(4-N-pyrrolidinocarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926563)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN2,N4-bis(4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith pyrrolidine gaveN2,N4-bis[4-(N-pyrrolidino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.90 (s, 1H), 7.50 (bd, 2H, J=7.8 Hz), 7.41 (bd, 2H,J=7.2 Hz), 6.93 (m, 4H), 6.73 (s, 1H), 6.64 (s, 1H), 4.65 (s, 1H), 4.65(s, 1H), 3.54 (m, 8H), 1.96 (m, 4H), 1.87 (m, 4H).

7.3.490N4-(3-tert-Butylpheny)-N2-[3-(N-1,3-dihydroxypropyl-2-amino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R940296)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3-tert-butylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand 2-amino-1,3-propanediol were reacted to giveN4-(3-tert-butylpheny)-N2-[-3-(1,3-dihydroxypropyl-2-amino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 20.26 min.; purity: 97.67%; MS (m/e): 484 (M⁺); 485(MH⁺); ¹H NMR (DMSO-d6): δ 9.75 (1H, s), 9.57 (1H, s), 8.25 (1H, m),7.92 (1H, m), 7.62 (2H, m), 7.37 (3H, m), 7.23 (1H, m), 6.66 (1H, m),4.46 (2H, s), 3.87 (1H, m), 3.55 (4H, m), 1.36 (9H, s).

7.3.491 N2-[3-(N-2,3-Dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-(3-isopropylphenyl)-2,4-pyrimidinediamineR940290

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-isopropylphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand 3-amino-1,2-propanediol were reacted to giveN2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl)-5-fluoro-N4-(3-isopropylphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 20.04 min.; purity: 98%; MS (m/e): 470 (MH⁺); ¹H NMR(DMSO-d6): δ 9.54 (1H, s), 9.41 (1H, s), 8.22 (1H, m), 7.95 (1H, m),7.85 (1H, d, J=10 Hz), 7.58 (1H, s), 7.43-7.32 (3H, m), 7.25 (1H, t,J=7.75 Hz), 7.06 (1H, d, J=7.75 Hz), 6.64 (1H, d, J=10 Hz), 4.47 (2H,s), 3.38 (4H, m), 3.16 (1H, m), 2.96 (1H, m), 1.28 (6H, d, J=6.9 Hz).

7.3.4925-Fluoro-N4-(3-isopropylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineR940288

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-isopropylphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to give5-fluoro-N4-(3-isopropylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 23.43 min.; purity: 99%; MS (m/e): 409 (M⁺), 411 (MH⁺);¹H NMR (DMSO-d6): δ 9.90 (1H, s), 9.74 (1H, s), 8.28 (1H, d, J=4.8 Hz),8.06 (1H, m), 7.78 (1H, d, J=7.2 Hz), 7.58 (1H, s), 7.4-7.3 (3H, m),7.24 (1H, t, J=8.4 Hz), 7.00 (1H, d, J=7.25 Hz), 6.70 (1H, d, J=7.25Hz), 4.44 (2H, s), 2.93 (1H, sept, J=6.9 Hz), 2.74 (3H, d, J=4.8 Hz),1.27 (6H, d, J=6.9 Hz).

7.3.4935-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-dimethylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926718)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamineand dimethylamine were reacted to yield5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-dimethylamino)carbonylbenzofuran-5-yl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.06 (d, 1H, J=2.1 Hz), 7.91 (d, 1H, J=3.6 Hz), 7.57(t, 1H, J=2.4 Hz), 7.37 (d, 1H, J=9.0 Hz), 7.28 (s, 1H), 7.19 (t, 1H,J=7.8), 7.06 (s, 1H), 6.82-6.76 (m, 2H), 6.71 (dd, 1H, J=2.4 and 7.8Hz), 3.31 (s, 3H), 3.09 (s, 3H); ¹⁹F NMR (CDCl₃): −47292; LCMS: ret.time: 17.29 min.; purity: 92%; MS (m/e): 408 (MH⁺).

7.3.494N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R945149)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(700 mg, 1.6 mmol) and piperazine (4 g, 46 mmol) gaveN4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(520 mg, 66%). ¹H NMR (CD₃OD): δ 6 2.22 (s, 3H), 2.75 (t, J=5.4 Hz, 4H),3.40 (t, J=4.8 Hz, 2H), 3.54 (t, J=5.1 Hz, 2H), 4.62 (s, 2H), 6.57 (ddd,J=1.5, 2.7 and 7.5 Hz, 1H), 7.09 (dt, J=1.5 and 8.1 Hz, 1H), 7.14 (t,J=7.8 Hz, 1H), 7.28 (t, J=2.1 Hz, 1H), 7.31 (dd, J=0.9 and 2.7 Hz, 1H),7.50 (d, J=2.7 Hz, 1H), 7.88 (d, J=3.9 Hz, 1H); ¹⁹F NMR (282 MHz,CD₃OD): δ −168.63; LCMS: ret. time: 14.99 min.; 93.88%; MS (m/e): 486.96(MH⁺).

7.3.495N4-(4-tert-Butylphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926713)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(4-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yieldN4-(4-tert-butylphenyl)-5-fluoro-N2-[2-(N-methylaminocarbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.05 (d, 1H, J=2.4 Hz), 7.88 (d, 1H, J=4.2 Hz), 7.57(d, 2H, J=8.7 Hz), 7.51-7.41 (m, 2H), 7.34-7.31 (m, 3H), 2.94 (s, 3H),1.33 (s, 9H); ¹⁹F NMR (CD₃OD): −47682; LCMS: ret. time: 23.02 min.;purity: 90%; MS (m/e): 434 (MH⁺).

7.3.496N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926796)

In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,5-dimethoxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyridinediaminewith methylamine hydrochloride gaveN4-(3,5-dimethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.92 (d, 1H, J=4.2 Hz), 7.42 (t, 1H, J=1.8 Hz), 7.12(m, 2H), 6.91 (d, 1H, J=2.4 Hz), 6.59 (m, 1H), 6.22 (t, 1H, J=1.8 Hz),4.35 (s, 2H), 3.69 (s, 6H), 2.81 (s, 3H); LCMS: ret. time: 18.35 min.;purity: 93%; MS (m/e): 428 (MH⁺).

7.3.4975-Ethoxycarbonyl-N4-(3,4-ethylenedioxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926800)

In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-ethoxycarbonyl-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-2,4-pyridinediaminewith methylamine hydrochloride gave5-ethoxycarbonyl-N4-(3,4-ethylenedioxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.05 (s, 1H), 9.34 (s, 1H), 8.69 (s, 1H), 7.95 (d,1H, J=4.8 Hz), 7.34 (dd, 1H, J=1.2 and 7.8 Hz), 7.25 (bs, 2H), 7.13 (t,1H, J=8.1 Hz), 7.00 (bd, 1H, J=9 Hz), 6.81 (d, 1H, J=8.7 Hz), 6.59 (dd,1H, J=1.5 and 8.4 Hz), 4.32 (s, 2H), 4.30 (q, 2H, J=7.2 Hz), 4.21 (s,4H), 2.63 and 2.62 (2s, 3H), 1.31 (t, 3H, J=7.2 Hz); LCMS: ret. time:24.12 min.; purity: 91%; MS (m/e): 481 (MH⁺).

7.3.498N4-(3,5-Dimethoxyphenyl)-5-ethoxycarbonyl-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926801)

In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxyphenyl)]-2,4-pyrimidinediamine,the reaction ofN4-(3,5-dimethoxyphenyl)-5-ethoxycarbonyl-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-2,4-pyridinediaminewith methylamine hydrochloride gaveN4-(3,5-dimethoxyphenyl)-5-ethoxycarbonyl-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.20 (s, 1H), 9.96 (s, 1H), 8.73 (s, 1H), 7.90 (bs,1H), 7.36 (d, 1H, J=8.7 Hz), 7.28 (bs, 1H), 7.12 (t, 1H, J=7.5 Hz), 6.84(s, 2H), 6.59 (dd, 1H, J=1.8 and 8.1 Hz), 6.25 (t, 1H, J=2.4 Hz), 4.31(m, 4H), 3.67 (s, 6H), 2.63 and 2.62 (2s, 3H), 1.31 (t, 3H, J=7.2 Hz);LCMS: ret. time: 25.50 min.; purity: 96%; MS (m/e): 482 (MH⁺).

7.3.499N4-(4-tert-Butylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926714)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(4-tert-butylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yieldN4-(4-tert-butylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.90 (d, 1H, J=3.3 Hz), 7.61 (d, 2H, J=8.7 Hz),7.40-7.33 (m, 3H), 7.14-7.11 (m, 2H), 6.62-6.57 (m, 1H), 4.36 (s, 2H),2.79 (s, 3H), 1.31 (s, 9H); ¹⁹F NMR (CD₃OD): −47514; LCMS: ret. time:23.70 min.; purity: 93%; MS (m/e): 424 (MH⁺).

7.3.500N4-(3-Hydroxyphenyl)-5-trifluoromethyl-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926742)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3-hydroxyphenyl)-5-trifluoromethyl-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yieldN4-(3-hydroxyphenyl)-5-trifluoromethyl-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 19.11 min.; purity: 99%; MS (m/e): 434 (MH⁺).

7.3.5015-Fluoro-N4-[(1H)-indol-6-yl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926745)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[(1H)-indol-6-yl]-4-pyrimidineamine and3-(N-methylamino)carbonylmethyleneoxyaniline were reacted to yield5-fluoro-N4-[(1H)-indol-6-yl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 17.41 min.; purity: 93%; MS (m/e): 407 (MH⁺).

7.3.502N4-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R945156)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and piperazine gaveN4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD3OD): δ 2.23 (s, 6H), 3.24 (m, 4H), 3.71 (s, 3H), 3.72-3.81(m, 4H), 4.75 (s, 2H), 6.81 (dt, J=1.2 and 8.1 Hz, 1H), 7.10-7.13 (m,2H), 7.24 (d, J=8.7 Hz, 1H), 7.29 (s, 2H), 7.98 (d, J=4.8 Hz, 1H); ¹⁹FNMR (282 MHz, CD₃OD): δ −163.88; LCMS: ret. time: 15.94 min.; purity:100%; MS (m/e): 481.12 (MH⁺).

7.3.503N4-(3-tert-Butylphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofur-5-yl]-2,4-pyrimidinediamineR940291

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to giveN4-(3-tert-butylphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofur-5-yl]-2,4-pyrimidinediamine.LCMS: ret. time: 23.05 min.; purity: 100%; MS (m/e): 434 (MH⁺); ¹H NMP(DMSO-d6): δ 9.6 (1H, s), 9.57 (1H, s), 8.75 (1H, m), 8.25 (1H, s), 8.15(1H, s), 7.93 (1H, d, J=8.5 Hz), 7.47 (3H, m), 7.44 (1H, s), 7.36 (1H,t, J=8.5 Hz), 7.25 (1H, d, J=8.5 Hz), 2.89 (3H, d, J=4.5 Hz), 1.33 (9H,s).

7.3.504N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926505)

In like manner to preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxy)phenyl)-2,4-pyrimidinediamineand 2-hydroxyethylamine gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.87 (d, 1H, J=3.6 Hz), 7.37 (t, 1H, J=1.8 Hz), 7.24(d, 1H, J=2.4 Hz), 7.13 (m, 2H), 7.08 (dd, 1H, J=2.1 and 8.1 Hz), 6.77(m, 1H), 4.38 (s, 2H), 4.22 (s, 3H), 3.63 (t, 2H), 3.40 (t, 2H, J=6 Hz);LCMS: ret. time: 16.72 min.; purity: 98%; MS (m/e): 456 (MH⁺).

7.3.5055-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926746)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand 3-amino-1,2-propanediol were reacted to yield5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 12.84 min.; purity: 96%; MS (m/e): 444 (MH⁺).

7.3.5065-Fluoro-N2-[2-(2-hydroxy-1,1-dimethylethylamino)carbonylbenzofuran-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926715)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamineand 2-amino-2-methylpropanol were reacted to yield5-fluoro-N2-[2-(2-hydroxy-1,1-dimethylethylamino)carbonylbenzofuran-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.41 (s, 1H), 9.28 (s, 1H), 9.22 (s, 1H), 8.18 (t,1H, J=2.4, Hz), 8.09 (d, 1H, J=3.6 Hz), 7.56 (dd, 1H, J=2.4 and 8.7 Hz),7.47 (d, 1H, J=8.7 Hz), 7.32 (s, 1H), 7.26-7.21 (m, 1H), 7.13-7.07 (m,2H), 6.53 (d, 1H, J=8.7 Hz), 5.05 (t, 1H, J=5.7 Hz), 3.46 (d, 2H, J=5.7Hz), 1.32 (s, 6H); LCMS: ret. time: 17.93 min.; purity: 97%; MS (m/e):452 (MH⁺).

7.3.5075-Fluoro-N4-(4-isopropoxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926730)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yield5-fluoro-N4-(4-isopropoxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.93 (d, 1H, J=3.0 Hz), 7.47 (d, 2H, J=9.3 Hz), 7.42(t, 1H, J=1.8 Hz), 7.17 (t, 1H, J=8.1 Hz), 7.10 (bs, 1H), 7.00 (dd, 1H,J=1.8 and 9.3 Hz), 6.89 (d, 2H, J=9.3 Hz), 6.80 (d, 1H, J=1.8 Hz), 6.58(bs, 1H), 6.50 (dd, 1H, J=1.5 and 8.1 Hz), 4.51 (2q, 1H, J=5.7 Hz), 4.44(s, 2H), 2.88 (d, 3H, J=4.5 Hz), 1.33 (d, 6H, J=5.7 Hz); ¹⁹F NMR(CDCl₃): −47198; LCMS: ret. time: 19.66 min.; purity: 97%; MS (m/e): 426(MH⁺).

7.3.5085-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R945170)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)methyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN2-(4-cyanomethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 2.91 (d, J=5.1 Hz, 3H), 4.48 (s, 2H), 6.61 (ddd,J=0.9, 2.7 and 8.1 Hz, 1H), 6.63 (br, 1H), 6.76 (d, J=3.0 Hz, 1H),6.84-6.89 (m, 4H), 7.18 (t, J=8.1 Hz, 1H), 7.44 (d, J=8.7 Hz, 2H), 7.51(t, J=2.1 Hz, 1H), 7.92 (d, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ −167.70;LCMS: ret. time: 14.32 min.; purity: 100%; MS (m/e): 383.98 (MH⁺).

7.3.5095-Fluoro-N4-(3-isopropoxyphenyl)-N2-[2-(N-morpholino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926489)

In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-fluoro-N4-(3-isopropoxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidineaminewith morpholine gave5-fluoro-N4-(3-isopropoxyphenyl)-N2-[2-(N-morpholino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.01 (d, 1H, J=1.2 Hz), 7.95 (bs, 1H), 7.43-7.38 (m,2H), 7.29 (s, 1H), 7.25-7.11 (m, 4H), 6.97 (bs, 1H), 6.73 (m, 1H), 6.67(bdd, 1H), 4.48 (sept, 1H, J=5.7 Hz), 3.87 (m, 4H), 3.79 (m, 4H), 1.30(d, 6H, J=5.7 Hz), LCMS: ret. time: 22.12 min.; purity: 98%; MS (m/e):492 (MH⁺).

7.3.5105-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926772)

In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-fluoro-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediaminewith piperazine gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.91 (d, 1H, J=3.6 Hz), 7.42 (t, 1H, J=2.4 Hz),7.20-7.07 (m, 5H), 6.55 (m, 2H), 4.63 (s, 2H), 3.54 (t, 2H, J=6 Hz),3.40 (t, 2H, J=5.1 Hz), 2.76 (t, 4H, J=5.4 Hz); LCMS: ret. time: 12.98min.; purity: 92%; MS (m/e): 439 (MH⁺).

7.3.5115-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926506)

In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewith 2-hydroxyethylamine gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 14.95 min.; purity: 96%; MS (m/e): 414 (MH⁺).

7.3.5125-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926508)

In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of 5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-ethoxy ormethoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine withmethylamine hydrochloride gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.64 (bs, 1H), 9.58 (bs, 1H), 8.15 (d, 1H, J=4.2Hz), 7.95 (bd, 1H), 7.25 (bd, 2H, J=6.6 Hz), 7.16-7.07 (m, 4H), 6.53 (m,2H), 4.35 (s, 2H), 2.64 and 2.62 (2s, 3H); LCMS: ret. time: 15.66 min.;purity: 98%; MS (m/e): 384 (MH⁺).

7.3.5135-Fluoro-N4-[3,4-(1,1,2,2-tetrafluoroethylendioxy)phenyl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926732)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[3,4-(1,1,2,2-tetrafluoroethylendioxy)phenyl]-4-pyrimidineamineand methylamine hydrochloride were reacted to yield5-fluoro-N4-[3,4-(1,1,2,2-tetrafluoroethylendioxy)phenyl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.65 (s, 1H), 9.37 (s, 1H), 8.16 (d, 1H, J=3.6 Hz),8.14 (d, 1H, J=2.4 Hz), 7.97 (d, 1H, J=4.8 Hz), 7.65 (dd, 1H, J=2.4 and8.7 Hz), 7.41 (d, 1H, J=9.3 Hz), 7.34 (t, 1H, J=2.4 Hz), 7.27 (d, 1H,J=8.1 Hz), 7.13 (t, 1H, J=8.1 Hz), 6.51 (dd, 1H, J=2.1 and 7.5 Hz), 4.36(s, 2H), 2.63 (d, 3H, J=4.8 Hz); ¹⁹F NMR (DMSO-d6): −25765 (pent,2F),−25830 (pent, 2F), −46309; LCMS: ret. time: 24.85 min.; purity: 95%;MS (m/e): 497 (MH⁺).

7.3.514N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R940254)

In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,5-dimethyl-4-hydroxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith morpholine gaveN4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-(N-morpholinocarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 18.38 min.; purity: 92%; MS (m/e): 468 (MH⁺); 1H NMP(DMSO-d6): δ 9.20 (1H, s), 9.10 (1H, s), 8.15 (1H, s), 8.11 (1H, d,J=3.9 Hz), 7.43 (1H, d, J=8.1 Hz), 7.32 (3H, m), 7.14 (1H, t, J=8.1 Hz),6.54 (1H, dd, J=8.1 and 2.0 Hz), 4.77 (2H, s), 3.64 (4H, m), 3.54-3.45(4H, m), 2.24 (6H, s).

7.3.515N4-(3-tert-Butylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R940276)

In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3-tert-butylphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith methylamine hydrochloride gaveN4-(3-tert-butylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 22.90 min.; purity: 99%; MS (m/e): 424 (MH⁺); 1H NMP(DMSO-d6): δ 9.46 (1H, s), 9.34 (1H, s), 8.08 (1H, d, J=3.9 Hz), 7.90(1H, m), 7.30 (1H, d, J=8.1 Hz), 7.46 (1H, m), 7.26 (1H, m), 7.20 (2H,m), 7.10-7.03 (2H, m), 6.47 (1H, d, J=8.1 Hz), 4.26 (2H, s), 2.59 (3H,d, J=4.5 Hz), 1.20 (9H, s).

7.3.516N4-(3-tert-Butylphenyl)-N2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R940277)

In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3-tert-butylphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith 2,3-dihydroxypropylamine gaveN4-(3-tert-butylphenyl)-N2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: retn. time: 20.46 min.; purity: 100%; MS (m/e): 484 (MH⁺); 1H NMP(DMSO-d6): δ 9.38 (1H, s), 9.29 (1H, s), 8.20 (1H, d, J=3.9 Hz), 8.00(1H, d, J=8.3 Hz), 7.93 (1H, t, J=5.5 Hz), 7.60 (1H, m), 7.47 (1H, m),7.41-7.17 (4H, m), 6.59 (1H, dd, J=8.3 and 2 Hz), 3.43 (2H, s), 3.39(4H, m), 3.16 (1H, m), 1.36 (9H, s).

7.3.517N4-(3,3-Dihydroisobenzofuran-1-one-6-yl)-N2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamineR940293

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2-[3-(ethoxycarbonylmethyleneoxy)phenyl]-N4-(3,3-dihydroisobenzofuran-1-one-6-yl)-5-fluoro-2,4-pyrimidinediamineand 3-amino-1,2-propanediol were reacted toN4-(3,3-dihydroisobenzofuran-1-one-6-yl)-N2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 13.92 min.; purity: 92%; MS (m/e): 483 (M⁺); 1H NMP(DMSO-d6): δ 9.80 (1H, s), 9.46 (1H, s), 8.37-8.27 (2H, m), 8.21 (1H,s), 7.96 (1H, t, J=4.6 Hz), 7.24 (1H, d, J=9 Hz), 7.44 (1H, s), 7.37(1H, d, J=9 Hz), 7.23 (1H, t, J=8 Hz), 6.60 (1H, dd, J=7 and 3.75 Hz)5.49 (2H, s), 4.46 (2H, s), 3.38 (4H, m), 3.2-3.1 (1H, m).

7.3.518N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926733)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-dimethoxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yieldN4-(3,4-dimethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.95 (d, 1H, J=3.6 Hz), 7.45 (t, 1H, J=1.8 Hz),7.21-7.17 (m, 2H), 7.05 (dd, 1H, J=2.7 and 8.7 Hz), 6.96-6.90 (m, 2H),6.87 (d, 1H, J=9.0 Hz), 6.72 (d, 1H, J=2.4 Hz), 6.67-6.58 (m, 1H), 6.52(dd, 1H, J=3.6 and 8.1 Hz), 4.39 (s, 2H), 3.89 (s, 3H), 3.78 (s, 3H),2.90 (d, 3H, J=4.8 Hz); LCMS: ret. time: 17.09 min.; purity: 98%; MS(m/e): 428 (MH⁺).

7.3.519 N2-[3-(N-2,3-Dihydroxypropylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926734)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-dimethoxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand 3-amino-1,2-propanediol were reacted to yieldN2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 8.05 (d, 1H, J=4.2 Hz), 7.38-7.34 (m, 2H), 7.31-7.26(m, 2H), 7.07 (t, 1H, J=8.4 Hz), 6.89 (d, 1H, J=8.7 Hz), 6.46 (dd, 1H,J=2.4 and 8.4 Hz), 4.36 (s, 2H), 3.72 (s, 3H), 3.68 (s, 3H), 3.32-3.24(m, 3H), 3.03 (dd, 1H, J=6.9 and 13.5 Hz); ¹⁹F NMR (DMSO-d6): −46574;LCMS: ret. time: 14.85 min.; purity: 94%; MS (m/e): 488 (MH⁺).

7.3.5205-Fluoro-N4-(3-methoxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926738)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-methoxyphenyl)-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yield5-fluoro-N4-(3-methoxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 18.40 min.; purity: 98%; MS (m/e): 398 (MH⁺).

7.3.521 N2-[3-(N-2,3-Dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-(3-methoxyphenyl)-2,4-pyrimidinediamine(R926739)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-N4-(3-methoxyphenyl)-2,4-pyrimidinediamineand 3-amino-1,2-propanediol were reacted to yieldN2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-(3-methoxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 16.66 min.; purity: 99%; MS (m/e): 458 (MH⁺).

7.3.522N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R945140)

In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and piperazine gaveN4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD3OD): δ 2.18 (s, 6H), 2.72 (q, J=5.1 Hz, 4H), 3.32 (t, 2H),3.52 (t, J=5.1 Hz, 2H), 4.55 (s, 2H), 6.56 (ddd, J=1.2, 2.4 and 8.1 Hz,1H), 7.03 (ddd, J=1.2, 1.8 and 8.1 Hz, 1H), 7.11 (t, J=8.1 Hz, 1H), 7.20(s, 2H), 7.35 (t, J=2.1 Hz, 1H), 7.84 (d, J=3.9 Hz, 1H); ¹⁹F NMR (282MHz, CD₃OD): δ −168.78; LCMS: ret. time: 14.32 min.; purity: 88.37%; MS(m/e): 467.06 (MH⁺).

7.3.5235-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-morpholino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926488)

In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediaminewith morpholine gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-morpholino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.19 (t, 1H, J=1.5 Hz), 7.90 (d, 1H, J=3.9 Hz), 7.44(d, 2H, J=0.9 hz), 7.28 (s, 1H), 7.21 (t, 1H, J=2.4 Hz), 7.15 (t, 1H,J=7.5 Hz), 7.08 (m, 1H), 7.61 (bd, 1H, J=6.9 Hz), 3.8 (m, 4H), 3.65 (m,4H); LCMS: ret. time: 17.21 min.; purity: 83%; MS (m/e): 450 (MH⁺).

7.3.5245-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926493)

In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediaminewith methylamine hydrochloride gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.71 (d, 1H, J=4.8 Hz), 8.00-7.92 (m, 2H), 7.56-7.52(m, 1H), 7.44-7.39 (m, 2H), 7.12 (m, 2H), 6.69 (bdd, 1H), 2.96 and 2.94(2s, 3H).

7.3.5255-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-2-hydroxyethylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926497)

In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediaminewith 2-hydroxyethylamine gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-2-hydroxyethylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.18 (d, 1H, J=1.8 Hz), 7.80 (bs, 1H), 7.60 (m, 1H),7.34-7.16 (m, 3H), 7.10 9t, 1H, 8.4 Hz), 6.85 (bdd, 1H), 6.62 (dd, 1H,J=1.5 and 8.1 Hz), 3.70 (t, 2H, J=4.8 Hz), 3.52 (t, 2H, J=4.0 Hz); LCMS:ret. time: 14.49 min.; purity: 97%; MS (m/e): 424 (MH⁺).

7.3.5265-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926500)

In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediaminewith piperazine gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.19 (t, 1H, J=1.2 Hz), 7.90 (d, 1H, J=3.9 Hz), 7.43(d, 2H, J=1.2 Hz), 7.25-7.06 (m, 4H), 6.59 (m, 1H), 3.80 (m, 4H), 2.95(m, 4H); LCMS: ret. time: 12.97 min.; purity: 79%; MS (m/e): 449 (MH⁺).

7.3.5275-Cyano-N4-(3-hydroxyphenyl)-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R925844)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-N-methylaminocarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-cyano-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediaminewith methylamine hydrochloride gave5-cyano-N4-(3-hydroxyphenyl)-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 18.83 min.; purity: 96%; MS (m/e): 391 (MH⁺).

7.3.5285-Cyano-N4-[4-(N-cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R925845)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-cyano-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediaminereacted with cyclopropylmethylamine to give5-cyano-N4-[4-(N-cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 22.47 min.; purity: 100%; MS (m/e): 431 (MH⁺).

7.3.5295-Cyano-N4-(3-hydroxyphenyl)-N2-[4-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R925846)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-cyano-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediaminereacted with 2,3-dihydroxypropylamine to give5-cyano-N4-(3-hydroxyphenyl)-N2-[4-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 15.84 min.; purity: 100%; MS (m/e): 451 (MH⁺).

7.3.5305-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3-trifluoromethylphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-N4-(3-trifluoromethylphenyl)-2,4-pyrimidineaminewith methylamine hydrochloride gave5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)]-N4-(3-trifluoromethylphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 21.98 min., purity: 86%, MS (m/e): 436 (MH⁺).

7.3.531N4-[4-(4,5-Dichloro-1H-imidazol-1-ylphenyl)]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926812)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN-4-[4-(4,5-dichloro-1H-imidazol-1-ylphenyl)]-5-fluoro-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine with methylamine hydrochloride gaveN4-[4-(4,5-dichloro-1H-imidazol-1-ylphenyl)]-5-fluoroN2-(3-[N-methylamino)carbonylmethylene oxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 21.02 min., purity: 100%, MS (m/e): 502 (MH⁺).

7.3.532N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-methylaminocarbonyllindol-7-yl)-2,4-pyridinediamine(R926815)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-N4-(3-trifluorophenyl)-2,4-pyrimidineaminewith methylamine hydrochloride gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-methylaminocarbonyllindol-7-yl)-2,4-pyridinediamine.LCMS: ret. time: 17.97 min., purity: 97%, MS (m/e): 435 (MH⁺).

7.3.533N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926484)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN2-(3-ethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand morpholine gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.94 (bs, 1H), 7.35 (t, 1H, J=2.4 Hz), 7.24 (m, 1H),7.19 (t, 1H, J=8.1 Hz), 7.10 (bdd, 1H, J=6.9 Hz), 6.95 (m, 2H), 6.85 (d,1H, J=8.1 Hz), 6.94 (s, 1H), 6.58 (dd, 1H, J=1.8 and 2.8 Hz), 4.64 (s,2H), 4.27 9s, 4H), 3.62 (m, 4H), 3.55 (m, 4H); LCMS: ret. time: 18.45min.; purity: 100%; MS (m/e): 482 (MH⁺).

7.3.534N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-morpholino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926492)

In like manner to preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuron-5-yl)-2,4-pyrimidinediaminewith morpholine gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-morpholino)carbonylbenzofuron-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.27 (s, 1H), 9.17 (s, 1H), 8.14 (d, 1H, J=2.4 Hz),8.05 (d, 1H, J=5.6 Hz), 7.58-7.46 (m, 2H), 7.27 (m, 1H), 7.15 (dd, 1H,J=2.4 and 9 Hz), 6.80 9m, 1H), 4.24 (s, 4H), 3.80-3.45 (m, 8H); LCMS:ret. time: 19.97 min.; purity: 76%; MS (m/e): 492 (MH⁺).

7.3.535N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926496)

In like manner to preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamineand methylamine hydrochloride gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.06 (s, 1H), 7.85 (d, 1H, J=3.3 Hz), 7.42 (d, 2H,J=1.2 Hz), 7.35 (s, 1H), 7.29 (d, 1H, J=2.4 Hz). 6.99 (dd, 1H, J=3.3 and8.7 Hz), 6.78 (d, 1H, J=8.7 Hz), 4.24 (s, 4H), 2.94 (s, 3H); LCMS: ret.time: 18.05 min.; purity: 99%; MS (m/e): 436 (MH⁺).

7.3.536N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-2-hydroxyethylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926498)

In like manner to preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediaminewith 2-hydroxyethylamine yieldedN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-2-hydroxyethylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.07 (d, 1H, J=1.2 Hz), 7.86 (d, 1H, J=3.9 Hz), 7.43(d, 2H, J=1.5 Hz), 7.38 (s, 1H), 7.29 (d, 1H, J=2.4 Hz). 6.98 (dd, 1H,J=2.1 and 9 Hz), 6.78 (d, 1H, J=8.7 Hz), 4.23 (s, 4H), 3.72 (t, 2H,J=5.7 Hz), 3.53 (t, 2H, J=6.0 Hz); LCMS: ret. time: 16.21 min.; purity:97%; MS (m/e): 466 (MH⁺).

7.3.537N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926499)

In like manner to preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamineand piperazine yieldedN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.26 (s, 1H), 9.16 (s, 1H), 8.12 (d, 1H, J=1.8 Hz),8.04 (d, 1H, J=3.6 Hz), 7.49 (d, 2H), 7.30 (d, 1H, J=2.4 Hz), 7.20 (s,1H), 7.15 (bdd, 1H, J=3 Hz), 6.79 (d, 1H, J=8.7 Hz), 4.22 (s, 4H), 2.48(s, 3H); LCMS: ret. time: 14.61 min.; purity: 94%; MS (m/e): 491 (MH⁺).

7.3.538N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926503)

In like manner to preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-methoxycarbonymethyleneoxyphenyl)-2,4-pyrimidinediamineand piperazine were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 9.14 (bs, 2H), 8.04 (d, 3.6 Hz), 7.32-7.20 (m, 4H),7.06 (t, 1H, J=8.1 Hz), 6.79 (d, d, 1H, J=9 Hz), 6.43 (bd, 1H, J=9.9Hz), 4.64 (s, 2H), 4.20 (bs, 4H), 3.29 (m, 4H), 2.59 (m, 4H); LCMS: ret.time: 14.92 min.; purity: 99%; MS (m/e): 481 (MH⁺).

7.3.539N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-2-hydroxy-1,1-dimethylethylamino)carboxymethyleneoxyphenyl]-2,4-pyrimidinediamine(R926764)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand 2-amino-2-methylpropanol gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-2-hydroxy-1,1-dimethylethylamino)carboxymethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.95 (d, 1H, J=2.7 Hz), 7.47 (t, 1H, J=2.4 Hz), 7.20(t, 1H, J=8.1 Hz), 7.03 (dd, 1H, J=1.2 and 8.1 Hz), 6.98 (dd, 1H, J=3and 8.2 Hz), 6.93 (s, 1H), 6.84 (d, 1H, J=8.7 Hz), 6.66 (d, 1H, J=3 Hz),6.57 (bs, 1H), 6.53 (m, 1H), 4.65 (m, 1H), 4.39 (s, 2H), 4.28 (s, 4H),3.63 (d, 2H, J=5.7 Hz), 1.31 (s, 6H); LCMS: ret. time: 19.19 min.;purity: 89%; MS (m/e): 484 (MH⁺).

7.3.540N2-[3-(N-Cyclohexylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926765)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand cyclohexylamine gave N2-[3-(N-cyclohexylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.94 (d, 1H, J=3.3 Hz), 7.41 (t, 1H, J=2.4 Hz), 7.28(d, 1H, J=2.4 Hz), 7.20 (t, 1H, J=7.5 Hz), 7.04 (dd, 1H, J=1.2 and 8.1Hz), 6.95 (m, 2H), 6.85 (d, 1H, J=8.7 Hz), 6.68 (d, 1H, J=3.0 Hz), 6.53(dd, 1H, J=2.4 and 8.4 Hz), 6.45 (bd, 1H, J=8.1 Hz), 4.43 (s, 2H), 4.24(s, 4H), 3.85 (m, 1H), 1.90 (m, 2H), 1.75-1.55 (m, 2H), 1.45-1.05 (m,6H); LCMS: ret. time: 23.70 min.; purity: 97%; MS (m/e): 494 (MH⁺).

7.3.541N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[N-methyl-N-(2-hydroxyethyl)amino]carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926766)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand N-methyl-N-2-hydroxyethylamine gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[N-methyl-N-(2-hydroxyethyl)amino]carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.93 (d, 1H, J=3 Hz), 7.92 (bs, 1H), 7.35 (t, 1H,J=2.4 Hz), 7.18 (m, 1H), 7.06 (dd, 1H, J=1.2 and 8.7 Hz), 6.97 (t, 1H,J=2.4 Hz), 6.94 (m, 1H), 6.85 (d, 1H, J=8.7 Hz), 6.70 (bd, 1H), 6.59(dd, 1H, J=1.8 and 8.1 Hz), 4.66 (s, 2H), 4.28 (s, 4H), 3.79 (t, 2H,J=5.4 Hz), 3.56 (t, 3H, J=5.4 Hz), 3.10 (s, 3H); LCMS: ret. time: 16.64min.; purity: 97%; MS (m/e): 470 (MH⁺).

7.3.542N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-homopiperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926767)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamineand homopiperazine gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-homopiperazinocarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.27 (s, 1H), 9.17 (d, 1H, J=1.2 Hz), 8.14 (s, 1H),8.05 (d, 1H, J=3.6 Hz), 7.54-7.46 (m, 2H), 7.30 (d, 1H, J=2.4 Hz), 7.24(s, 1H), 7.17 (dd, 1H, J=2.4 and 8.7 Hz), 6.80 (d, 1H, J=8.7 Hz), 4.22(s, 4H), 3.79 (m, 2H), 3.65 (m, 2H), 3.01 (m, 2H), 2.89 (m, 2H), 1.90(m, 1H), 1.80 (m, 1H); ¹⁹F NMR (DMSO-d6): −46687; LCMS: ret. time: 14.99min.; purity: 77%; MS (m/e): 505 (MH⁺).

7.3.543N4-(3,4-Ethylenedioxyphenyl)-N2-[3-(N,N-dimethylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R925755)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand N,N-dimethylamine hydrochloride gaveN4-(3,4-ethylenedioxyphenyl)-N2-[3-(N,N-dimethylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.16 (d, 1H, J=1.2 Hz), 9.15 (s, 1H), 8.04 (d, 1H),J=5.6 Hz), 7.30-7.21 (m, 4H), 7.06 (t, 1H, J=9 Hz), 6.78 (d, 1H, J=9Hz), 6.43 (m, 1H), 4.65 (s, 2H), 4.21 (s, 4H), 2.94 (s, 3H), 2.82 (s,3H); LCMS: ret. time: 18.70 min.; purity: 83%; MS (m/e): 440 (MH⁺).

7.3.544N2-[3-[N,N-Bis-(2-hydroxyethylamino)]carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926781)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand N,N-bis(hydroxyethyl)amine gaveN2-[3-[N,N-bis-(2-hydroxyethylamino)]carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.86 (d, 1H, J=3.6 Hz), 7.25 (m, 2H), 7.17-7.03 (m,3H), 6.78 (d, 1H, J=9 Hz), 6.58 (bd, 1H), 4.80 (s, 2H), 4.23 (s, 4H),3.71 (t, 4H, J=4.8 Hz), 3.53 (t, 2H, J=6 Hz), 3.49 (t, 3H, J=5.4 Hz);LCMS: ret. time: 16.25 min.; purity: 94%; MS (m/e): 500 (MH⁺).

7.3.545 N2-[3-(N-2,3-Dihydroxypropylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926782)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand 2,3-dihydroxypropylamine gaveN2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.86 (d, 1H, J=4.2 Hz), 7.37 (t, 1H, J=1.8 Hz), 7.24(d, 1H, J=2.4 Hz), 7.14 (m, 2H), 7.09 (dd, 1H, J=2.4 and 9 Hz), 6.78 (d,1H, J=8.7 Hz), 6.59 (m, 1H), 4.39 (s, 2H), 4.22 (s, 4H), 3.73 (m, 1H),3.48 (m, 4H); ¹⁹F NMR (CD₃OD): −47575; LCMS: ret. time: 15.97; purity:98%; MS (m/e): 486 (MH⁺).

7.3.546N2-[2-(N-2,3-Dihydroxypropylamino)carbonylbenzofuran-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926783)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamineand 2,3-dihydroxypropylamine gaveN2-[2-(N-2,3-dihydroxypropylamino)carbonylbenzofuran-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.86 (d, 1H, J=4.2 Hz), 7.35 (t, 1H, J=1.2 Hz), 7.24(d, 1H, J=3 Hz), 7.15 (m, 2H), 7.07 (dd, 1H, J=2.1 and 8.7 Hz), 6.78 (d,1H, J=8.7 Hz), 6.59 (m, 1H), 4.40 9s, 1H), 4.23 (s, 4H), 4.03 (t, 1H,J=5.7 Hz), 3.67 (d, 2H, 3.6 Hz), 3.65 (d, 2H, J=4.2 Hz); ¹⁹F NMR(CD₃OD): −47578; LCMS: ret. time: 15.72 min.; purity: 99%; MS (m/e): 486(MH⁺).

7.3.547 N2-[3-(N-1,3-Dihydroxy-2-propylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926784)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethylenedioxyphenyl)-2,4-pyrimidinediamineand 2-amino-1,3-propanediol gaveN2-[3-(N-1,3-dihydroxy-2-propylamino)carbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.08 (bd, 1H), 7.86 (bs, 1H), 7.44 (s, 2H), 7.39 (s,1H), 7.29 (d, 1H, J=2.4 Hz), 6.97 (dd, 1H, J=2.4 and 8.7 Hz), 6.78 (d,1H, J==8.7 Hz), 4.24 (s, 4H), 3.84 (m, 1H), 3.56 (m, 2H), 3.44 (m, 2H);LCMS: ret. time: 16.63 min.; purity: 97%; MS (m/e): 496 (MH⁺).

7.3.548N2-[2-(N-1,3-Dihydroxy-2-propylamino)carbonylbenzofuran-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926785)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamineand 2-amino-1,3-propanediol gaveN2-[2-(N-1,3-dihydroxy-2-propylamino)carbonylbenzofuran-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.08 (t, 1H, J=1.8 Hz), 7.86 (d, 1H, J=3.9 Hz), 7.45(s, 2H), 7.41 (s, 1H), 7.29 (d, 1H, J=2.4 Hz), 6.97 (dd, 1H, J=3 and 8.7Hz), 6.77 (d, 1H, J=8.7 Hz), 4.24 (s, 4H), 4.19 (t, 1H, J=5.7 Hz), 3.75(d, 4H, J=5.4 Hz); ¹⁹F NMR (CD₃OD): −47745; LCMS: ret. time: 15.09 min.,purity: 97%; MS (m/e): 496 (MH⁺).

7.3.549N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R940265)

In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3-chloro-4-hydroxy-5-methylphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith morpholine gaveN4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 18.66 min.; purity: 92%; MS (m/e): 487 (M⁺), 489 (MH⁺);¹□□□□□ (DMSO-d6): 9.28 (2H, s), 9.01 (1H, s), 8.17 (1H, d, J=3.6 Hz),7.65 (1H, d, J=2.4 Hz), 7.5 (1H, d, J=2.7 Hz), 7.42 (1H, d, J=6.6 Hz),7.29 (1H, s), 7.18 (1H, t, J=8.1 Hz), 6.57 (1H, dd, J=6.6 and 2.2 Hz),4.79 (2H, s), 3.67 (4H, m), 3.52 (4H, m), 2.29 (3H, s).

7.3.550N4-(3,5-Dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950187)

N4-(3,5-Dichlorophenyl-4-hydroxy)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(0.5 g, 1.1 mmol) was dissolved in EtOH:morpholine (4 ml:4 ml) and themixture was refluxed for 1 day (100° C. oil-bath temperature). Themixture was cooled to 22° C., diluted with water and brine, filtered,and dried under reduced pressure to giveN4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.35 (s, 1H), 9.22 (s, 1H), 8.09 (d, 1H, J=3.6 Hz),7.94 (m, 1H), 7.75 (m, 1H), 7.27 (m, 1H), 7.18 (m, 1H), 7.12 (t, 1H,J=8.4 Hz), 6.44 (m, 1H), 4.64 (s, 2H), 3.39 (m, 4H), 2.68 (m, 4H); LCMSpurity: 92.6%; MS (m/e): 507.89 (M⁺, 100).

7.3.551N4-(3,5-Dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950188)

In like manner to the preparation ofN4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,5-dichloro-4-hydroxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamineand piperazine were reacted to prepareN4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 15.26 min.; purity: 88.5%; MS (m/e): 506.89 (MH⁺).

7.3.552N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[3-(N-methylamino)carbonylmethyeleneoxyphenyl]-2,4-pyrimidinediamine(R926776)

In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3-ethoxycarbonylmethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith methylamine hydrochloride gaveN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[3-(N-methylamino)carbonylmethyeleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 16.94 min.; purity: 73%; MS (m/e): 426 (MH⁺).

7.3.553N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-(4-methylaminocarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945173)

In a manner analogous to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-(4-methylaminocarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine,N4-(4-cyanomethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand methylamine hydrochloride salt gaveN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-(4-methylaminocarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (acetone-d₆): δ 2.80 (d, 3H), 4.21-4.28 (m, 4H), 4.47 (s, 2H),6.71 (d, J=8.7 Hz, 1H), 6.96 (d, J=9.0 Hz, 2H), 7.06 (dd, J=2.7 and 9.0Hz, 1H), 7.41 (d, J=2.4 Hz, 1H), 7.74 (d, J=9.0 Hz, 2H), 7.93 (d, J=3.6Hz, 1H), 8.20 (br, 1H, NH), 8.41 (br, 1H, NH); ¹⁹F NMR (282 MHz,acetone-d₆): δ −169.05; LCMS: ret. time: 17.47 min.; purity: 98.99%; MS(m/e): 425.89 (MH⁺).

7.3.554N2-[4-(2-N,N-Dimethylaminoethyl)oxyphenyl]-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R909253)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N2-chloro-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-4-pyrimidineamine and 4-(2-N,N-dimethylaminoethyl)oxyanilinewere reacted to yieldN2-[4-(2-N,N-dimethylaminoethyl)oxyphenyl]-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.0 (d, 1H J=4 Hz), 7.42 (m, 2H), 7.24 (m, 2H), 7.05(m, 2H), 6.85 (m, 1H), 4.39 (s, 2H), 4.30 (m, 2H), 3.66 (m, 2H), 3.04(s, 6H), 2.83 (s, 3H); LCMS: ret. time: 14.0 min.; purity: 96%; MS(m/e): 455 (MH⁺).

7.3.555N2-(1,4-Benzoxazin-6-yl)-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R909247)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N2-chloro-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-4-pyrimidineamine and 6-amino-1,4-benzoxazine were reacted toyieldN2-(1,4-benzoxazin-6-yl)-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H (DMSO-d6): δ 8.0 (d, 1H), 7.6 (m, 1H), 7.42 (m, 1H), 7.20 (m, 1H),6.95 (m, 1H), 6.76 (m, 1H), 6.56 (m, 1H), 4.43 (s, 2H), 4.05 (m, 2H),3.25 (s, 3H), 3.13 (m, 2H); LCMS: ret time: 17.67 min.; MS (m/e): 425(MH⁺).

7.3.556N2-(4-Dihydrobenzofuranyl)-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R909249)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N2-chloro-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-4-pyrimidineamine and 5-amino-2,3-dihydrobenzofuran werereacted to yieldN2-(4-dihydrobenzofuranyl)-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine. ¹H NMR (DMSO-d6): δ 8.09 (d, 1H), 8.00(m, 1H), 7.42 (m, 2H), 7.05 (m, 1H), 6.96 (m, 1H), 6.76 (m, 1H), 6.58(m, 1H), 4.53 (m, 2H), 4.25 (s, 2H), 3.15 (m, 2H), 2.70 (m, 3H); LCMS:ret time: 19.24 min; MS (m/e): 410 (MH⁺).

7.3.557N2-(3-tert-Butylphenyl)-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R940267)

In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN2-(3-tert-butylphenyl)-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith methylamine hydrochloride gaveN2-(3-tert-butylphenyl)-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 22.22 min.; purity: 97%; MS (m/e): 424 (MH⁺); ¹H NMP(CDCl₃): δ 7.98 (2H, m), 7.76 (2H, m), 7.56 (1H, t, J=1.3 Hz), 7.28-7.22(1H, m), 7.04 (1H, d, J=7.8 Hz), 6.90 (1H, dd, J=9 Hz, J=1.3 Hz), 6.80(1H, 2.6 Hz), 6.66 (1H, dd, J=9 and 2.6 Hz), 6.46 (1H, s), 4.53 (2H, s),2.88 (3H, d, J=5.1 Hz), 1.31 (9H, s).

7.3.558N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926491)

In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN2-(3,4-ethylenedioxyphenyl)-N4-(2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediaminewith methylamine hydrochloride gaveN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.10 (s, 1H), 7.94 (d, 1H, J=5.1 Hz), 7.59 (s, 2H),7.44 (s, 1H), 6.96 (d, 1H, J=2.4 Hz), 6.82 (d, 1H, J=8.4 Hz), 6.76 (dd,1H, J=3.6 and 8.1 Hz), 4.22 (s, 2H), 4.21 (s, 2H), 2.95 (s, 3H); LCMS:ret. time: 17.76 min.; purity: 97%; MS (m/e): 436 (MH⁺).

7.3.559N2-(3,5-Dimethoxyphenyl)-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926810)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine,the reaction ofN2-(3,5-dimethoxyphenyl)-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith methylamine hydrochloride gaveN2-(3,5-dimethoxyphenyl)-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.93 (d, 1H, J=3.9 Hz), 7.72 (t, 1H, J=1.8 Hz),7.27-7.19 9m, 2H), 6.88 (d, 2H, J=2.4 Hz), 6.72 (m, 1H), 6.01 (t, 1H,J=2.4 Hz), 4.44 (s, 2H), 3.67 (s, 6H), 2.80 (s, 3H).

7.3.5605-Bromo-N2-(3,4-ethylenedioxyphenyl)-N4-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R925851)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-bromo-N2-(3,4-ethylenedioxyphenyl)-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yield5-bromo-N2-(3,4-ethylenedioxyphenyl)-N4-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.01 (s, 1H), 7.48 (d, 2H, J=8.7 Hz), 7.09 (d, 1H,J=3.0 Hz), 7.08 (d, 2H, J=8.7 Hz), 6.81 (dd, 1H, J=8.7 Hz), 6.64 (d, 1H,J=8.7 Hz), 4.52 (s, 2H), 4.20 (bs, 4H), 2.83 (s, 3H); LCMS: ret. time:19.13 min.; purity: 94%; MS (m/e): 487 (MH⁺).

7.3.561N2-(3-Hydroxyphenyl)-5-trifluoromethyl-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926741)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2-(3-hydroxyphenyl)-5-trifluoromethyl-N4-(3-N-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yieldN2-(3-hydroxyphenyl)-5-trifluoromethyl-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 18.52 min.; purity: 96%; MS (m/e): 434 (MH⁺).

7.3.562N2,N4-Bis[4-(N-n-butylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine(R925860)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-cyano-2,4-pyrimidinediamineand n-butylamine were reacted to yieldN2,N4-bis[4-(N-n-butylamino)carbonylmethyleneoxyphenyl)-5-cyano-2,4-pyrimidinediamine. ¹H NMR (DMSO-d6): δ 9.77 (bs,1H), 9.38 (bs, 1H), 8.42 (s, 1H), 8.09 (t, 1H, J=5.4 Hz), 8.02 (t, 1H,J=5.7 Hz), 7.48-7.34 (m, 4H), 6.93 (d, 2H, J=9.3 Hz), 6.82-6.72 (m, 2H),4.47 (s, 2H), 4.38 (s, 2H), 3.14-3.06 (m, 4H), 1.42-1.33 (m, 4H),1.28-1.18 (m, 4H), 0.83 (t, 6H, J=6.9 Hz); LCMS: ret. time: 26.40 min.;purity: 97%; MS (m/e): 546 (MH⁺).

7.3.563N2,N4-Bis[4-(N-isopropylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine(R925861)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-cyano-2,4-pyrimidinediamineand isopropylamine were reacted to yieldN2,N4-bis[4-(N-isopropylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine. ¹H NMR (DMSO-d6): δ 8.41 (s,1H), 7.90 (d, 1H, J=7.5 Hz), 7.81 (d, 1H, J=7.5 Hz), 7.50-7.36 (m, 4H),6.93 (d, 2H, J=8.7 Hz), 6.84-6.75 (m, 2H), 4.45 (s, 2H), 4.36 (s, 2H),3.99-3.87 (m, 2H), 1.08 (d, 6H, J=3.0 Hz), 1.06 (d, 6H, J=2.4 Hz); LCMS:ret. time: 23.45 min.; purity: 89%; MS (m/e): 518 (MH⁺).

7.3.564 N2,N4-Bis[4-(N-n-propylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine (R925853)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-cyano-2,4-pyrimidinediamineand n-propyl amine were reacted to yieldN2,N4-bis[4-(N-n-propylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.78 (bs, 1H), 9.38 (bs, 1H), 8.41 (s, 1H), 8.07(dt, 2H, J=6.0 and 22.5 Hz), 7.48-7.36 (m, 4H), 6.93 (d, 2H, J=8.7 Hz),6.78 (d, 2H, J=8.1 Hz), 4.48 (s, 2H), 4.39 (s, 2H), 3.07 (2q, 4H, J=7.2Hz), 1.47-1.38 (m, 4H), 0.90-0.77 (m, 6H); LCMS: ret. time: 23.67 min.;purity: 94%; MS (m/e): 519 (MH⁺).

7.3.565N2,N4-Bis[4-(N-morphonlino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine(R925854)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-cyano-2,4-pyrimidinediamineand morpholine were reacted to yieldN2,N4-bis[4-(N-morphonlino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.78 (bs, 1H), 9.31 (bs, 1H), 8.41 (s, 1H), 7.43 (d,4H, J=8.1 Hz), 6.89 (d, 2H, J=9.3 Hz), 6.75 (d, 2H, J=8.4 Hz), 4.84 (s,2H), 4.74 (s, 2H), 3.76 (t, 4H, J=5.1 Hz), 3.62-3.50 (m, 4H), 3.49-3.38(m, 4H), 3.08-3.01 (m, 4H); LCMS: ret. time: 19.25 min.; purity: 89%; MS(m/e): 574 MH⁺).

7.3.566N2,N4-Bis[4-(N-piperidino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine(R925855)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-cyano-2,4-pyrimidinediamineand piperidine were reacted to yieldN2,N4-bis[4-(N-piperidino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine.¹H NMR (acetone-d₆): δ 8.86 (bs, 1H), 8.48 (bs, 1H), 8.34 (s, 1H),7.61-7.50 (m, 4H), 6.98 (d, 2H, J=8.7 Hz), 6.90 (d, 2H, J=9.3 Hz), 4.84(s, 2H), 4.75 (s, 2H), 3.59-3.48 (m, 8H), 1.68-1.44 (m, 12H); LCMS: ret.time: 24.76 min.; purity: 98%; MS (m/e): 571 (MH⁺).

7.3.567N2,N4-Bis[4-(N-cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine(R925859)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-cyano-2,4-pyrimidinediamineand cyclopropylmethylamine were reacted to yieldN2,N4-bis[4-(N-cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.78 (bs, 1H), 9.36 (bs, 1H), 8.41 (s, 1H), 8.18 (t,1H, J=5.1 Hz), 8.10 (t, 1H, J=5.1 Hz), 7.52-7.38 (m, 4H), 6.94 (d, 2H,J=8.7 Hz), 6.84-6.76 (m, 2H), 4.48 (s, 2H), 4.40 (s, 2H), 3.00 (q, 4H,J=6.3 Hz), 0.97-0.88 (m, 2H), 0.40-0.33 (m, 4H), 0.18-0.03 (m, 4H); ¹⁹FNMR (CDCl₃): LCMS: ret. time: 24.58 min.; purity: 100%; MS (m/e): 543(MH⁺).

7.3.568N4-(3-Aminophenyl)-N2-(1,4-benzoxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R950254)

N4-(3-Nitrophenyl)-N2-[(2H)1,4-benzoxazin-3(4H)-one-6-yl]-5-fluoro-2,4-pyrimidinediamine (940 mg, 2.5 mmol) andPd/C 10% (300 mg, 50% water content) were suspended in EtOH (7 mL) and10% aqueous HCl (5 mL) and hydrogenated in a Parr apparatus for 3 hours(22° C., 60 psi). The suspension was filtered over celite andneutralized by addition of K₂CO₃. The solvents were removed and theresulting black slurry was suspended in MeOH. Silica gel (4 g) was addedand the volatiles were removed under reduced pressure. The residue wassubjected to column chromatography on silica gel (CHCl₃-Acetone, 2:1) togive 186 mg ofN4-(3-aminophenyl)-N2-(1,4-benzoxazin-6-yl)-5-fluoro-2,4-pyrimidinediamineas brownish solid. ¹H NMR (DMSO-d6): δ 8.92 (s, 1H), 8.64 (s, 1H), 7.95(d, 1H, J=3.6 Hz), 7.11 (s, 1H), 6.84-6.95 (m, 3H), 6.66 (dd, 1H, J=2.4,9.0 Hz), 6.46 (d, 1H, J=8.1 Hz), 6.28 (d, 1H, J=8.1 Hz), 5.62 (s, 1H),4.98 (s, 2H), 4.03 (m, 2H), 3.31 (m, 2H); LCMS purity: 98.4%; MS (m/e):352.7 (M⁺, 100).

7.3.569N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-2-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950200)

N2-(3-Ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(50 mg, 0.11 mmol) was dissolved in EtOH:4-(2-aminoethyl)morpholine (0.5ml:0.5 ml) and the mixture was refluxed for 3 hours (100° C. oil-bathtemperature). The mixture was cooled to 22° C., diluted with water andwashed with EtOAc. The organic phase was dried over MgSO₄, concentratedunder educed pressure, and the residue was subjected to columnchromatography on silica gel (CHCl₃:Acetone, 2:1) to giveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-2-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine. ¹H NMR(DMSO-d6+CD₃OD): δ 7.92 (d, 1H, J=4.1 Hz), 7.31 (d, 1H, J=2.3 Hz), 7.20(dd, 1H, J=2.7, 8.8 Hz), 6.87-6.99 (m, 2H), 6.74 (d, 1H, J=8.8 Hz), 6.09(m, 1H), 4.19 (m, 4H), 3.38 (m, 4H), 3.16 (t, 2H, J=6.3 Hz), 2.28 (t,2H, J=6.3 Hz); LCMS purity: 99.2%; MS (m/e): 524.01 (M⁺, 100).

7.3.570N4-(3,4-Ethylenedioxyphenyl)-N2-[3-N-methylamino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine(R950191)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand methylamine were reacted to prepareN4-(3,4-ethylenedioxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 17.32 min.; purity: 99.3%; MS (m/e): 425.04 (MH⁺).

7.3.571N2-[3-(N-Amino)carbonylmethyleneaminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950192)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand aqueous ammonia were reacted to prepareN2-[3-(N-amino)carbonylmethyleneaminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 16.59 min.; purity: 98.8%; MS (m/e): 411.02 (MH⁺).

7.3.572N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950193)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand morpholine were reacted to prepareN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 18.70 min.; purity: 85.8%; MS (m/e): 481.05 (MH⁺).

7.3.573N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N—(N-methyl)-piperazino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950194)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand N-methylpiperazine were reacted to prepareN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N—(N-methyl)piperazino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine. LCMS: ret. time: 15.75min.; purity: 99.1%; MS (m/e): 494.06 (MH⁺).

7.3.574N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-2-hydroxyethyleneamino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine(R950195)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand 2-aminoethanol were reacted to prepareN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-2-hydroxyethyleneamino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 16.23 min.; purity: 97.3%; MS (m/e): 455.02 (MH⁺).

7.3.575N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)ethyleneaminocarbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950196)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand N-methyl-ethylen-1,2-diamine were reacted to prepareN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)ethyleneaminocarbonylmethyleneaminophenyl]-2,4-pyrimidinediamine. LCMS: ret. time: 15.34min.; purity: 98.2%; MS (m/e): 468.06 (MH⁺).

7.3.576N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine(R950197)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand piperazine were reacted to prepareN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 15.38 min.; purity: 93.2%; MS (m/e): 479.99 (MH⁺).

7.3.577N2-[3-(N-Benzylamino)ethyleneaminocarbonylmethyleneaminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950198)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand N-benzyl-ethylen-1,2-diamine were reacted to prepareN2-[3-(N-benzylamino)ethyleneaminocarbonylmethyleneaminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 17.70 min.; purity: 92.5%; MS (m/e): 544.04 (MH⁺).

7.3.578N2-[3-(N,N′-Bis(2-N-hydroxyethyl)amino)carbonylmethyleneaminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950199)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand N,N′-bis(2-hydroxyethylene)amine were reacted toN2-[3-(N,N′-bis(2-N-hydroxyethyl)amino)carbonylmethyleneaminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 15.81 min.; purity: 99.4%; MS (m/e): 499.01 (MH⁺).

7.3.5795-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950217)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand methylamine were reacted to prepare5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 14.41 min.; purity: 93.0%; MS (m/e): 383.02 (MH⁺).

7.3.580N2-(3-Aminocarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R950219)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand aqueous ammonia were reacted to prepareN2-(3-aminocarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 14.23 min.; purity: 95.0%; MS (m/e): 369.03 (MH⁺).

7.3.581N2-[3-(N,N-Dimethylamino)carbonylmethyleneaminophenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R950220)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand dimethylamine were reacted to prepareN2-[3-(N,N-dimethylamino)carbonylmethyleneaminophenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 16.59 min.; purity: 96.5%; MS (m/e): 397.06 (MH⁺).

7.3.5825-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-morpholino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950221)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand morpholine were reacted to prepare5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-morpholino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 16.29 min.; purity: 91.5%; MS (m/e): 439.03 (MH⁺).

7.3.5835-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-piperazino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950222)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand piperazine were reacted to prepare5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-piperazino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 13.04 min.; purity: 89.9%; MS (m/e): 438.06 (MH⁺).

7.3.5845-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[N—(N-methyl)piperazino]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950223)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand N-methylpiperazine were reacted to prepare5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-[N—(N-methyl)piperazino]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 12.06 min.; purity: 98.7%; MS (m/e): 452.06 (MH⁺).

7.3.5855-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950224)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand 2-aminoethanol were reacted to prepare5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 13.28 min.; purity: 97.3%; MS (m/e): 413.04 (MH⁺).

7.3.5865-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)ethylamino]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950225)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand N-methyl-ethylen-1,2-diamine were reacted to prepare5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)ethylamino]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 12.31 min.; purity: 94.7%; MS (m/e): 426.01 (MH⁺).

7.3.5875-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-2-morpholinoethylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950226)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand N-morpholinylethylamine were reacted to prepare5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-2-morpholinoethylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 12.66 min.; MS (m/e): 482.39 (MH⁺).

7.3.588 R935184:5-Fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N2-[4-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediaminewas reacted with Me₂NH.HCl and i-Pr₂NEt in methanol to produce5-fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 6.91 min.; purity: 98%; MS (m/e): 440 (MH⁺).

7.3.589 R935196:N2-[3-(1-Bis(N-methylaminocarbonyl)ethoxy)phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidineamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-[3-(1-bis(ethyloxycarbonyl)ethoxy)phenyl]-5-fluoro-N2-[4-isopropoxyphenyl)-2,4-pyrimidinediaminewas reacted with Me₂NH.HCl and i-Pr₂NEt in presence of methanol toproduceN2-[3-(1-bis(N-methylaminocarbonyl)ethoxy)phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidineamine.¹H NMR (DMSO-d6): δ 9.18 (s, 1H), 9.15 (s, 1H), 8.07 (app qt, 2H, J=4.7Hz), 8.01 (d, 1H, J=3.5 Hz), 7.65-7.62 (m 2H), 7.36 (br s, 1H), 7.28(dd, 1H, J=1.1 and 8.2 Hz), 7.03 (t, 1H, J=8.2 Hz), 6.87 (d, 2H, J=8.8Hz), 6.35 (dd, 1H, J=1.1 and 8.8 Hz), 4.54 (q, 1H, J=6.4 Hz), 2.62 (d,6H, J=4.7 Hz), 1.49 (s, 3H), 1.23 (d, 6H, J=5.8 Hz). LCMS: ret. time:19.40 min.; purity: 94%; MS (m/e): 497 (MH⁺).

7.3.590 R935202:5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediaminewas reacted with Me₂NH.HCl to give5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.21 (s, 1H), 9.19 (s, 1H), 8.06 (d, 1H, J=4.1 Hz),7.94 (q, 1H, J=3.5 Hz), 7.42-7.38 (m, 2H), 7.30 (d, 2H, J=7.6 Hz), 7.12(t, 1H, J=7.6 Hz), 6.89 (d, 1H, J=8.2 Hz), 6.47 (dd, 1H, J=2.3 and 8.8Hz), 4.33 (s, 2H), 4.11-4.03 (m, 4H), 2.63 (d, 3H, J=4.7 Hz)), 2.08-2.03(m, 2H). LCMS: ret. time: 17.33 min.; purity: 98%; MS (m/e): 440 (MH⁺).

7.3.591 R935206: N2,N4-Bis[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2,N4-Bis[1-(methoxycarbonyl)methyl-indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamineand was reacted with Me₂NH.HCl and i-PrN₂Et in presence of methanol toproduce N2,N4-bis[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.56 (s, 1H), 9.40 (s, 1H), 8.17 (d, 1H, J=3.5 Hz),8.12 (s, 1H), 7.99 (s, 1H), 7.96 (s, 2H), 7.90 (s, 2H), 7.66 (d, 1H,J=8.8 Hz), 7.56 (d, 1H, J=8.8 Hz), 7.49 (dd, 1H, J=1.7 and 8.8 Hz), 7.34(dd, 1H, J=1.7 and 8.8 Hz), 4.90 (s, 2H), 4.66 (s, 2H), 2.56 (d, 6H,J=4.11 Hz). LCMS: ret. time: 13.85 min.; purity: 98%; MS (m/e): 503(MH⁺).

7.3.592 R935212:N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamineand Me₂NH.HCl was reacted to produceN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.35 (s, 1H), 9.17 (s, 1H), 8.07 (d, 1H, J=4.8 Hz),7.92 (s, 1H), 7.89 (s, 1H), 7.66 (q, 1H, J=4.7 Hz), 7.54 (d, 1H, J=8.8Hz), 7.35-7.24 (m, 3H), 6.76 (d, 1H, J=8.8 Hz), 4.77 (s, 2H), 4.20 (s,4H), 2.57 (d, 3H, J=4.7 Hz). LCMS: ret. time: 15.82 min.; purity: 94%;MS (m/e): 450 (MH⁺).

7.3.593 R935213:N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-(N-methylamino)carbonyl-fur-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-methoxycarbonyl-fur-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediaminewas reacted with Me₂NH.HCl and i-Pr₂NEt. to giveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-(N-methylamino)carbonyl-fur-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.17 (s, 2H), 8.30 (q, 1H, J=4.7 Hz), 8.05 (d, 1H,J=3.5 Hz), 7.42 (s, 1H), 7.29-7.19 (m, 2H), 7.09 (t, 1H, J=8.2 Hz), 7.02(d, 1H, J=2.9 Hz), 6.76 (d, 1H, J=8.8 Hz), 6.67 (d, 1H, J=2.9 Hz), 6.54(dd, 1H, J=1.7 and 8.2 Hz), 4.94 (s, 2H), 4.21-4.18 (m, 4H), 2.70 (d,3H, J=4.7 Hz). LCMS: ret. time: 18.85 min.; purity: 91%; MS (m/e): 492(MH⁺).

7.3.594 R935216:5-Fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N2-[4-(methoxycarbonylmethyleneoxy)phenyl]-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provide5-fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxy)phenyl]-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine¹H NMR (DMSO-d6): δ 9.31 (s, 1H), 9.00 (s, 1H), 8.17 (s, 1H), 8.02 (d,1H, J=3.5 Hz), 7.99 (m, 1H), 7.93 (s, 1H), 7.59 (m, 2H), 7.52 (d, 2H,J=8.8 Hz), 6.78 (d, 2H, J=8.8 Hz), 4.36 (s, 2H), 4.03 (s, 3H), 2.63 (d,3H, J=4.7 Hz). LCMS: ret. time: 14.81 min.; purity: 99%; MS (m/e): 422(MH⁺).

7.3.595 R935217: N2,N4-Bis[1-(N-methylaminocarbonyl)methyl-indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2,N4-bis[1-(methoxycarbonyl)methyl-indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to produce N2,N4-bis[1-(N-methylaminocarbonyl)methyl-indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.35 (s, 1H), 9.15 (s, 1H), 8.09-8.06 (m, 2H),7.97-7.96 (m, 2H), 7.91 (s, 1H), 7.70 (s, 1H), 7.69 (s, 1H), 7.64-7.55(m, 2H), 7.48-7.40 (m, 2H), 5.06 (s, 2H), 4.97 (s, 2H), 2.62 (d, 3H,J=4.7 Hz), 2.61 (d, 3H, J=4.7 Hz). LCMS: ret. time: 12.54 min.; purity:95%; MS (m/e): 503 (MH⁺).

7.3.596N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926486)

A dry reaction vial equipped with a rubber septum was charged withN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(0.019 g, 0.04 mmol) and THF (1 mL). To this was added boranemethylsulfide complex (0.044 mL, 0.088 mmol) and stirred at room temperaturefor 2 h. The amount of boranemethyl sulfide complex was evaporated andthe reaction was quenched with MeOH (CAUTION: vigorous evolution ofhydrogen gas occurs during the addition of MeOH), heated for 30 min. Thesolvent was removed and again the residue was suspended in MeOH,extracted with EtOAc, EtOAc was evaporated and the residue was purifiedby preparative TLC to obtainN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.20 (s, 1H), 8.01 (d, 1H, J=6 Hz), 7.26-7.05 (m, 3H),7.05-6.97 (m, 3H), 6.82 (d, 1H, J=9.3 Hz), 6.67 (dd, 1H, J=1.8 and 8.1Hz), 4.44 (t, 2H), 4.27 (s, 4H), 4.14 (m, 2H), 3.76 (m, 2H), 3.22 (t,2H, J=5.4 Hz), 3.05 (m, 2H), 2.88 (m, 2H).

7.3.597N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-morpholinomethylene)benzofuran-5-yl]-2,4-pyrimidinediamine(R926490)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-morpholino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediaminewith boranemethyl sulfide complex gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-morpholinomethylene)benzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.65 (d, 2H, J=2.1 Hz), 8.30 (dd, 2H, J=2.1 and 9.6Hz), 7.73 (d, 2H, J=9.3 Hz), 7.49 (bs, 2H), 7.32 (m, 1H), 6.74 (m, 1H),4.24 (s, 4H), 3.97 (s, 2H), 3.78 (m, 4H), 3.56 (m, 4H).

7.3.598N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-methylamino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926510)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand boranemethyl sulfide complex gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-methylamino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.00 (d, 1H, J=5.2 Hz), 7.50-7.30 (m, 2H), 7.16-6.80(m, 5H), 4.28 (m, 1H), 4.27 (bs, 4H), 4.22 (m, 1H), 3.44 (m, 2H), 2.79(d, 3H, J=3 Hz); LCMS: ret. time: 15.64 min.; purity: 96%; MS (m/e): 412(MH⁺).

7.3.5995-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazinomethylene)benzofuran-5-yl]-2,4-pyrimidinediamine(R926770)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,the reaction of5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediaminewith boranemethyl sulfide complex gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazinomethylene)benzofuran-5-yl]-2,4-pyrimidinediamine.LCMS: ret. time: 12.06 min.; purity: 75%; MS (m/e): 435 (MH⁺).

7.3.600N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine(R940255)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewith boranemethyl sulfide complex gaveN4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 15.94 min.; purity: 99%; MS (m/e): 454 (MH⁺); ¹□□□□(DMSO-d6): δ 9.16 (1H, s), 9.07 (1H, s), 8.15 (1H, s), 8.11 (1H, d,J=3.9 Hz), 7.40-7.30 (4H, m), 7.13 (1H, t, 8.1 Hz), 6.55 (1H, dd, J=8.1Hz, 3.2 Hz), 4.01 (2H, t, J=5.7 Hz), 3.65 (4H, t, J=4.2 Hz), 2.72 (2H,t, J=5.7 Hz), 2.515 (4H, t, J=4.5 Hz), 2.24 (6H, s).

7.3.601N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethoxy]phenyl]-2,4-pyrimidinediaminebis Hydrogen Chloride Salt (R945142)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminewas treated with boranemethyl sulfide complex to giveN4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethyloxy]phenyl]-2,4-pyrimidinediamine,which was then treated with 4N HCl in dioxane (3 mL) followedcrystallization from MeOH/EtOAc to giveN4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethoxy]phenyl]-2,4-pyrimidinediaminebis Hydrogen Chloride Salt. ¹H NMR (CD₃OD): δ 2.17 (s, 6H), 3.66 (m,10H), 4.26 (t, J=4.5 Hz, 2H), 6.93 (dd, J=1.5, 7.2 Hz, 1H), 7.10-7.13(m, 2H), 7.17 (s, 2H), 7.31 (t, J=8.4 Hz, 1H), 7.98 (d, J=6.0 Hz, 1H);¹⁹F NMR (282 MHz, CD₃OD): δ −162.93; LCMS: ret. time: 13.25 min.;purity: 96.08%; MS (m/e): 453.09 (MH⁺).

7.3.602N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(2-hydroxyethyloxy)phenyl]-2,4-pyrimidinediamine(R945144)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,the reaction ofN2-(4-carboxymethyleneoxyphenyl)-N4-(3,4-ethylendioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand boranemethyl sulfide complex gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine.¹H NMR (acetone-d₆): δ 3.86 (t, J=4.8 Hz, 2H), 4.04 (t, J=4.8 Hz, 2H),4.28 (m, 4H), 6.78 (d, J=9.0 Hz, 1H), 6.86 (d, J=9.0 Hz, 2H), 7.18 (dd,J=2.7, 8.7 Hz, 1H), 7.47 (d, J=2.7 Hz, 1H), 7.63 (d, J=9.0 Hz, 2H), 7.91(d, J=3.6 Hz, 1H), 8.29 (br, 1H, NH), 8.31 (br, 1H, NH); ¹⁹F NMR (282MHz, acetone-d₆): δ −169.18; LCMS: ret. time: 17.41 min.; purity:98.36%; MS (m/e): 399.01 (MH⁺).

7.3.603N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethoxy]phenyl]-2,4-pyrimidinediamineDihydrochloride Salt (R945150)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,N4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminewas treated with boranemethyl sulfide complex to giveN4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethyloxy]phenyl]-2,4-pyrimidinediamine,which was then treated with 4N HCl in dioxane (3 mL) followedcrystallization from MeOH/EtOAc to giveN4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethoxy]phenyl]-2,4-pyrimidinediaminebis Hydrogen Chloride Salt. 1H NMR (CD₃OD): δ 2.21 (s, 3H), 3.72 (m,10H), 4.35 (t, J=4.5 Hz, 2H), 6.95 (dt, J=1.5 and 9.0 Hz, 1H), 7.11-7.14(m, 2H), 7.26 (dd, J=0.9 and 2.7 Hz, 1H), 7.34 (t, J=8.4 Hz, 1H), 7.50(d, J=2.4 Hz, 1H), 8.03 (d, J=5.4 Hz, 1H); ¹⁹F NMR (282 MHz, CD₃OD): δ−162.74; LCMS: ret. time: 14.50 min.; purity: 94.75%; MS (m/e): 472.98(MH⁺).

7.3.604N4-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethoxy]phenyl]-2,4-pyrimidinediamineDihydrochloride Salt (R945157)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,N4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminewas treated with boranemethyl sulfide complex to giveN4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethyloxy]phenyl]-2,4-pyrimidinediamine,which was then treated with 4N HCl in dioxane (3 mL) followedcrystallization from MeOH/EtOAc to giveN4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethoxy]phenyl]-2,4-pyrimidinediaminebis Hydrogen Chloride Salt. ¹H NMR (CD₃OD): δ 2.23 (s, 6H), 3.66 (m,10H), 3.72 (s, 3H), 4.31 (t, J=4.5 Hz, 2H), 6.95 (dd, J=1.8 and 8.4 Hz,1H), 7.09-7.15 (m, 2H), 7.27 (s, 2H), 7.32 (t, J=8.1 Hz, 1H), 8.01 (d,J=5.4 Hz, 1H); ¹⁹F NMR (282 MHz, CD₃OD): δ −162.71; LCMS: ret. time:16.41 min.; purity: 97.50%; MS (m/e): 467.12 (MH⁺).

7.3.605N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt (R926501)

The reaction of equivalent amount ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediaminewith hydrogen chloride (4M, dioxane) in methanol at 0° C. followed bydilution with dry ethyl ether or ethyl acetate gave the precipitate. Theresulting precipitate was isolated by filtration (and/or usingcentrifuse technique) to giveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt. ¹H NMR (CD₃OD): δ 7.97 (d, 1H, J=5.4 Hz), 7.92(d, 1H, J=1.8 Hz), 7.62 (d, 1H, J=8.2 Hz), 7.48 (s, 1H), 7.43 (dd, 1H,J=J=2.4 and 8.7 Hz), 7.17 (d, 1H, J=2.4 Hz), 6.98 (dd, 1H, J=2.4 and 8.7Hz), 6.77 (d, 1H, J=8.7 Hz), 4.13 (m, 4H), 4.22 (s, 4H), 3.38 (t, 4H,J=5.7 Hz); LCMS: ret. time: 15.12 min; purity: 89%; MS (m/e): 491 (MH⁺).

7.3.606N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt (R926504)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt, the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand hydrogen chloride gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine Hydrogen Chloride Salt. ¹H NMR(DMSO-d6): δ 9.6 (bs, 1H), 9.04 (bs, 1H), 8.12 (d, 1H, J=3.6 Hz),7.25-7.00 (m, 5H), 7.81 (d, 1H, J=8.7 Hz), 6.54 (d, 1H, J=8.4 Hz), 4.74(s, 2H), 4.22 (s, 4H), 3.64 (m, 4H), 3.11 (m, 4H); LCMS: ret. time:15.34 min.; purity: 100%; MS (m/e): 481 (MH⁺).

7.3.607N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-N-methylaminoethyl)phenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt (R926509)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt, the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-methylamino)ethyloxy]phenyl]-2,4-pyrimidinediaminewith hydrogen chloride (4M, dioxane) gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-methylamino)ethyloxy]phenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt. LCMS: ret. time: 15.88 min.; purity: 92%; MS(m/e): 412 (MH⁺).

7.3.608N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt (R926511)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt, the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-pyrimidinediamineand hydrogen chloride gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt. ¹H NMR (CD₃OD): δ 7.98 (d, 1H, J=5.4 Hz), 7.34(t, 1H, 8.4 Hz), 7.16-6.81 (m, 6H), 4.42 (m, 1H), 4.40 (m, 2H), 4.25 (m,5H), 4.10 (m, 2H), 3.90 (bs, 2H), 3.60 (m, 4H); LCMS: ret. time: 16.39min.; purity: 100%; MS (m/e): 468 (MH⁺).

7.3.609N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-homopiperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt (R926768)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt, the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-homopiperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediaminewith hydrogen chloride treatment gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-homopiperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt. ¹H NMR (DMSO-d6): δ 9.98 (bs, 1H), 9.05 (bs,1H), 8.18 (d, 1H, J=4.8 Hz), 8.01 (s, 1H), 7.58 (d, 1H, J=8.7 Hz), 7.50(bd, 1H), 7.35 (s, 1H), 7.24 (d, 1H, J=2.4 Hz), 7.11 (dd, 1H, J=3 and 9Hz), 6.80 (d, 1H, J=8.7 Hz), 4.22 (s, 4H), 4.20-3.60 (m, 8H), 3.20 (m,2H); LCMS: ret. time: 14.91 min.; purity: 86%; MS (m/e): 505 (MH⁺).

7.3.6105-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt R926502)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt,5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineupon treatment with hydrogen chloride (4M, dioxane) gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt. ¹H NMR (CDC₃OD): δ 8.00 (s, 1H), 7.89 (s, 1H),7.98 (s, 1H), 7.60 (d, 1H, J=8.7 Hz), 7.45 (m, 3H), 7.16 (t, 1H, J=8.1Hz), 7.10 (m, 1H), 7.02 (dd, 1H, J=1.2 and 7.2 Hz), 6.70 (dd, 1H, J=2.4and 8.4 Hz), 4.13 (m, 4H), 3.37 (t, 4H, J=5.4 Hz), 3.38 (t, 4H, J=5.7Hz); LCMS: ret. time: 13.40 min; purity: 79%; MS (m/e): 450 (MH⁺).

7.3.6115-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazinomethylene)benzofuran-5-yl]-2,4-pyrimidinediamineDihydrochloride Salt (R926769)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt, the reaction of5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazinomethylene)benzofuran-5-yl]-2,4-pyrimidinediaminewith hydrogen chloride (4M, dioxane) gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazinomethylene)benzofuran-5-yl]-2,4-pyrimidinediamineDihydrochloride Salt. ¹H NMR (CD₃OD): δ 8.00 (d, 1H), 7.85 (bd, 1H),7.75 (m, 3H), 7.60 (m, 2H), 7.40-7.15 (m, 4H), 7.05 (s, 1H), 7.00-6.800(m, 3H), 4.65 (dd, 2H), 3.60 (m, 8H).

7.3.6125-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt (R926773)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt,5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand hydrogen chloride (4M, dioxane) gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt. ¹H NMR (CD₃OD): δ 7.99 (d, 1H, J=5.1 Hz), 7.29(t, 1H, J=8.1 Hz), 7.21-7.05 (m, 5H), 6.83 (dd, 1H, J=2.4 and 8.7 Hz),6.77 (bd, 1H), 4.79 (s, 2H), 3.83 (m, 2H), 3.78 (m, 2H), 3.25 (m, 2H);LCMS: ret. time: 12.27 min.; purity: 91%; MS (m/e): 439 (MH⁺).

7.3.613 N2-[3-[2-(N,N-Dimethylamino)ethyloxy]phenyl]-N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineHydrogen Chloride Salt (R926771)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt, the treatment ofN4-(3,4-ethylenedioxyphenyl)-N2-[3-[2-(N,N-dimethylamino)ethyloxy]phenyl]-5-fluoro-2,4-pyrimidinediamine withequivalent amount of hydrogen chloride (4M, dioxane) gaveN4-(3,4-ethylenedioxyphenyl)-N2-[3-[2-(N,N-dimethylamino)ethyloxy]phenyl]-5-fluoro-2,4-pyrimidinediamine HydrogenChloride Salt. LCMS: ret. time: 15.37 min.; purity: 93%; MS (m/e): 426(MH⁺).

7.3.614N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt (R940256)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt, the reaction ofN4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-pyrimidinediaminewith hydrogen chloride (4M, dioxane) gaveN4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt. LCMS: ret. time: 15.78 min.; purity: 98%; MS(M/e): 454 (MH⁺); 1H NMP (DMSO-d6): δ 10.60 (1H, s), 9.58 (1H, s), 8.29(1H, s), 8.20 (1H, s), 7.43 (1H, d, J=9 Hz), 7.38-7.30 (3H, m), 7.24(1H, t, J=9 Hz), 6.70 (1H, d, J=9 Hz), 4.35 (2H, m), 4.05 (2H, m), 3.84(4H, m), 3.65-3.50 (2H, m), 3.26 (2H, m), 2.25 (6H, s).

7.3.615N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt (R940269)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt, the reaction ofN4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-pyrimidinediaminewith hydrogen chloride (4M, dioxane) gaveN4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt. LCMS: ret. time: 14.74 min.; purity: 96%; MS(m/e): 474 (M⁺), 475 (MH⁺); ¹H NMP (DMSO-d6): δ 10.03 (1H, s), 9.35 (2H,s), 9.06 (1H, s), 8.17 (1H, d, J=3.9 Hz), 7.67 (1H, m), 7.52 (1H, m),7.46 (1H, d, J=8.7 Hz), 7.39 (1H, s), 7.24 (1H, t, J=8.1 Hz), 6.66 (1H,d, J=8.1 Hz), 4.33 (1H, m), 4.07 (1H, d, J=13 Hz), 3.79 (1H, t, J=12.5Hz), 3.56 (4H, m), 3.49 (4H, m), 3.29 (1H, t, J=12.5 Hz), 2.29 (3H, s).

7.3.616N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt (R926816)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt, the treatment ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminewith equivalent amount of hydrohen chloride (4M, dioxane) gave theN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineHydrogen Chloride salt. LCMS: ret. time: 17.04 min., purity: 96%, MS(m/e): 426 (MH⁺).

7.3.617N4-(3,4-Ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine(R926696)

A dry reaction flask charged withN4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediaminewas reacted with diisobutylaluminum hydride (DIBALH) (5 equivalents) inCH₂Cl₂ at −78° C. (reaction was monitored by TLC) followed by treatmentwith Rochell's salt to yieldN4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.11 (s, 1H), 8.02 (d, 1H, J=3.3 Hz), 7.96 (t, 1H,J=1.8 Hz), 7.40-7.30 (m, 3H), 7.19 (dt, 1H, J=3.6 and 8.1 Hz), 6.78 (d,1H, J=8.7 Hz), 6.59 (s, 1H), 4.52 (d, 2H, J=5.1 Hz), 4.22 (s, 4H); ¹⁹FNMR (DMSO-d6): −46802; LCMS: ret. time: 19.14 min.; purity: 95%; MS(m/e): 409 (MH⁺).

7.3.6185-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(hydroxymethyl)-(1H)-indol-5-yl]-2,4-pyrimidinediamine(R926700)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(methoxycarbonyl)-(1H)-indol-5-yl]-2,4-pyrimidinediaminewas reduced with DIBALH to yield5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(hydroxymethyl)-(1H)-indol-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.81 (d, 1H, J=4.2 Hz), 7.23 (d, 1H, J=1.8 Hz),7.28-7.23 (m, 2H), 7.19 (t, 1H, J=2.4 Hz), 7.12 (dd, 1H, J=1.8 and 9.0Hz), 7.07 (t, 1H, J=8.4 Hz), 6.52 (ddd, 1H, J=1.2 and 8.1 Hz), 6.30 (s,1H), 4.71 (s, 2H); ¹⁹F NMR (CD₃OD): −47971; LCMS: ret. time: 15.36 min.;purity: 100%; MS (m/e): 366 (MH⁺).

7.3.6195-Fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-N4-[4-(isopropoxy)phenyl]-2,4-pyrimidinediamine(R926705)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine,5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to yield5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.83 (d, 1H, J=3.3 Hz), 7.81 (s, 1H), 7.50 (d, 2H,J=9.0 Hz), 7.29 (d, 1H, J=9.0 Hz), 7.22 (dd, 1H, J=2.4 and 8.7 Hz), 6.84(d, 2H, J=8.7 Hz), 6.56 (d, 1H, J=1.2 Hz), 4.64 (s, 2H), 4.56 (2q, 1H,J=5.7 Hz), 1.31 (d, 6H, J=6.0 Hz); ¹⁹F NMR (CD₃OD): −47926; LCMS: ret.time: 21.03 min.; purity: 99%; MS (m/e): 409 (MH⁺).

7.3.6205-Fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926707)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediaminewas reduced with DIBALH to yield5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.37 (s, 1H), 9.17 (s, 1H), 9.12 (s, 1H), 8.06 (d,1H, J=3.9 Hz), 8.01 (d, 1H, J=1.8 Hz), 7.41-7.35 (m, 2H), 7.26 (d, 1H,J=8.1 Hz), 7.11-7.05 (m, 2H), 6.60 (s, 1H), 6.51 (dd, 1H, J=2.4 and 8.4Hz), 5.41 (t, 1H, J=6.0 Hz), 4.51 (d, 2H, J=5.7 Hz); LCMS: ret. time:16.21 min.; purity: 95%; MS (m/e): 367 (MH⁺).

7.3.621N4-(4-tert-Butyl)phenyl)-5-fluoro-N2-[3-(2-hydroxyethyleneoxy)phenyl]-2,4-pyrimidinediamine(R926728)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine,N4-(4-tert-butylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBAL to yieldN4-(4-tert-butylphenyl)-5-fluoro-N2-[3-(2-hydroxyethyleneoxy)phenyl]-2,4-pyrimidinediamine. ¹H NMR (CDCl₃): δ 7.94 (d, 1H, J=3.0 Hz),7.54 (d, 2H, J=9.0 Hz), 7.37 (d, 2H, J=8.4 Hz), 7.29-7.35 (m, 1H),7.19-7.14 (m, 2H), 7.06 (d, 1H, J=8.1 Hz), 6.82 (d, 1H, J=2.7 Hz), 6.57(dd, 1H, J=2.4 and 8.1 Hz), 4.04-4.00 (m, 2H), 3.93-3.89 (m, 2H), 1.33(s, 9H); ¹⁹F NMR (CDCl₃): −47214; LCMS: ret. time: 22.39 min.; purity:94%; MS (m/e): 397 (MH⁺).

7.3.6225-(Hydroxymethyl)-N2-[3-(2-hydroxyethyleneoxy)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926735)

In a manner similar to the preparation ofN4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine,N4-(3-hydroxyphenyl)-5-methoxycarbonyl-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediaminewas reduced with DIBALH to yield5-(hydroxymethyl)-N2-[3-(2-hydroxyethyleneoxy)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.87 (s, 1H), 7.35 (t, 1H, J=1.5 Hz), 7.15-7.08 (m,5H), 6.57-6.50 (m, 2H), 4.56 (s, 2H), 3.92-3.86 (m, 2H), 3.84-3.79 (m,2H); LCMS: ret. time: 14.11 min.; purity: 89%; MS (m/e): 369 (MH⁺).

7.3.6235-Fluoro-N2-[3-(2-hydroxyethyleneoxy)phenyl]-N4-(3-isopropylphenyl)-2,4-pyrimidinediamineR940289

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-isopropylphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminereacted with DIBALH to give5-fluoro-N2-[3-(2-hydroxyethyleneoxy)phenyl]-N4-(3-isopropylphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 23.03 min.; purity: 93%; MS (m/e): 382 (M⁺), 384 (MH⁺);¹H NMP (DMSO-d6): δ 9.36 (1H, s), 9.24 (1H, s), 8.20 (1H, d, J=4.2 Hz),7.85 (1H, d, J=8.5 Hz), 7.57 (1H, s), 7.41 (1H, s), 7.33 (1H, t, J=8.5Hz), 7.17 (1H, t, J=8.5 Hz), 7.05 (1H, d, J=8.5 Hz), 6.56 (1H, dd, J=8.5Hz, J=2 Hz) 4.94 (1H, t, J=12 Hz), 3.94 (2H, t, J=4.7 Hz), 3.76 (2H, m),2.95 (1H, sept, J=6.9 Hz), 1.28 (6H, dd, J=6.9 Hz, J=0.6 Hz).

7.3.624N4-(3-tert-Butylphenyl)-5-fluoro-N2-[(2-hydroxymethylene)benzofur-5-yl]-2,4-pyrimidinediamineR940287

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,N4-(3-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediaminereacted with DIBALH to giveN4-(3-tert-butylphenyl)-5-fluoro-N2-[2-(hydroxymethylene)benzofur-5-yl]-2,4-pyrimidinediamine.LCMS: retn, time: 23.15 min.; purity: 99%; MS (m/e): 407 (MH⁺); 1H NMP(DMSO-d6): δ 9.34 (1H, s), 9.22 (1H, s), 8.18 (1H, d, J=3.9 Hz), 8.04(1H, s), 8.00 (1H, d, J=8.7 Hz), 7.60 (1H, t, J=2.1 Hz), 7.47 (2H, m),7.34 (1H, t, J=7.8 Hz), 7.21 (1H, d, J=8.7 Hz), 6.69 (1H, s), 5.54 (1H,t, J=5.8 Hz), 4.63 (2H, d, J=5.8 Hz), 1.35 (9H, s).

7.3.6255-Fluoro-N4-(3-isopropylphenyl)-N2-[(2-hydroxymethylene]benzofur-5-yl]-2,4-pyrimidinediamineR940286

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-isopropylphenyl)-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediaminereacted with DIBALH to give5-fluoro-N4-(3-isopropylphenyl)-N2-[(2-hydroxymethylene)benzofur-5-yl]-2,4-pyrimidinediamine.LCMS: ret. time: 21.93 min.; purity: 99%; MS (m/e): 393 (MH⁺); ¹H NMP(DMSO-d6): δ 9.33 (1H, s), 9.23 (1H, s), 8.18 (1H, d, J=3.9 Hz), 8.03(1H, s), 7.86 (1H, d, J=7.1 Hz), 7.57 (1H, s), 7.49 (2H, m), 7.33 (1H,t, J=7.1 Hz), 7.05 (1H, d, J=7.1 Hz), 6.69 (1H, s), 5.54 (1H, t, J=5.7Hz), 4.63 (2H, d, J=5.7 Hz), 2.90 (1H, sept, J=6.9 Hz), 1.26 (6H, d,J=6.9 Hz).

7.3.626N4-(3-tert-Butylphenyl)-5-fluoro-N2-[3-(2-hydroxyethyleneoxy)phenyl]-2,4-pyrimidinediamineR940282

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,N4-(3-tert-butylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminereacted with DIBALH to giveN4-(3-tert-butylphenyl)-5-fluoro-N2-[3-(2-hydroxyethyleneoxy)phenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 21.63 min.; Purity: 98%; MS (m/e): 396 (M⁺).

7.3.627N4-[3,4-Bis(hydroxymethyl)phenyl]-5-fluoro-N2-[3-(2-hydroxyethyleneoxy)phenyl]-2,4-pyrimidinediamine(R940292)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneoxyphenyl)-N4-[6-(3,3-dihydroisobenzofuranyl-1-one)]-5-fluoro-2,4-pyrimidinediaminereacted with DIBALH to giveN4-[3,4-bis(hydroxymethyl)phenyl]-5-fluoro-N2-[3-(2-hydroxyethyleneoxy)phenyl]-2,4-pyrimidinediamine.LCMS: retn, time: 13.06 min.; purity: 100%; MS (m/e): 400 (M⁺).

7.3.628 (R935149):N2-(3,4-Ethylenedioxyphenyl)-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine

2-Chloro-5-fluoro-N4-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-N2-(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediaminewas reduced with 10 eq. DIBALH (1.0 M in toluene) at 0° C. indichloromethane. Reaction was quenched with methanol, diluted withethylacetate followed by the addition of aqueous Rochelle's saltsolution, stirred at room temperature for 30 minutes followed by theaddition of anhydrous sodium sulfate. The solution was filtered throughCelite, concentrated and purified the concentrated by silica gel columnchromatography to furnish theN2-(3,4-ethylenedioxyphenyl)-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.01 (br s, 1H), 9.6 (br s, 1H), 8.13 (d, 1H, J=4.7Hz), 7.58 (d, 2H, J=8.2 Hz), 7.31 (d, 2H, J=8.8 Hz), 7.18 (d, 1H, J=2.3Hz), 6.88 (dd, 1H, J=2.3 and 8.8 Hz), 6.73 (d, 1H, J=8.8 Hz), 4.21-4.19(m, 4H), 3.56 (br s, 2H), 1.20 (s, 6H); LCMS: ret. time: 20.34 min.;purity: 98%; MS (m/e): 411 (MH⁺).

7.3.629 (R935151):5-Fluoro-N2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to provide5-fluoro-N2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.89 (d, 1H, J=2.9 Hz), 7.46 (d, 3H, J=8.8 Hz), 7.27(d, 2H, J=8.2 Hz), 6.89 (d, 2H, J=9.3 Hz), 6.68-6.65 (m, 1H), 4.53(septet, 1H, J=5.8 Hz), 3.57 (s, 2H), 1.36 (d, 6H, J=5.8 Hz), 1.31 (s,6H); LCMS: ret. time: 23.43 min.; purity: 99%; MS (m/e): 411 (MH⁺).

7.3.630 (R935153):5-Fluoro-N2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to provide5-fluoro-N2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.89 (d, 1H, J=2.9 Hz), 7.57 (s, 1H), 7.41 (d, 2H,J=8.8 Hz), 7.29 (d, 2H, J=8.2 Hz), 7.16 (d, 1H, J=8.2 Hz), 7.10 (d, 1H,J=8.8 Hz), 6.80-6.55 (m, 2H), 5.58 (s, 2H), 1.30 (s, 6H); LCMS: ret.time: 18.01 min.; purity: 98%; MS (m/e): 369 (MH⁺).

7.3.631 (R935154):N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine

In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to provideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.88 (d, 1H, J=3.8 Hz), 7.34 (t, 1H, J=2.3 Hz), 7.19(dd, 1H, J=2.3 and 8.2 Hz), 7.14 (d, 1H, J=7.6 Hz), 7.01-6.97 (m, 2H),6.84 (d, 1H, J=8.8 Hz), 6.53 (dd, 1H, J=1.7 and 7.6 Hz), 4.26 (s, 4H),3.98 (t, 2H, J=4.1 Hz), 3.89 (t, 2H, J=4.1 Hz); LCMS: ret. time: 18.36min.; purity: 99%; MS (m/e): 399 (MH⁺).

7.3.632 (R935155):5-Fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(methoxycarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediaminewas reduced to5-fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediaminewith DIBALH. ¹H NMR (CDCl₃): δ 7.73 (d, 1H, J=3.5 Hz), 7.33 (d, 2H,J=8.8 Hz), 7.15 (br s, 1H), 7.04 (app t, 2H, J=8.2 and 7.6 Hz), 6.78 (d,2H, J=8.8 Hz), 6.49 (d, 1H, J=7.6 Hz), 3.95 (t, 2H, J=4.7 Hz), 3.80 (t,2H, J=4.7 Hz); LCMS: ret. time: 14.49 min.; purity: 98%; MS (m/e): 357(MH⁺).

7.3.633 (R935156):5-Fluoro-N2-[3-(2-hydroxyethoxy)phenyl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(4-isopropoxyphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to provide5-fluoro-N2-[3-(2-hydroxyethoxy)phenyl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.90 (d, 1H, J=3.5 Hz), 7.45 (d, 2H, J=8.8 Hz), 7.34(t, 1H, J=2.3 Hz), 7.13 (t, 1H, J=8.2 Hz), 6.93 (m, 3H), 7.76 (d, 1H,J=2.3 Hz), 6.52 (dd, 1H, J=2.3 and 8.2 Hz), 4.52 (septet, 1H, J=5.7 Hz),3.95-3.85 (m, 4H), 1.34 (d, 6H, J=5.7 Hz); LCMS: ret. time: 21.17 min.;purity: 98%; MS (m/e): 399 (MH⁺).

7.3.634 (R935158):5-Fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N2-[4-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine

In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-[4-[1-ethoxycarbonyl1-methyl)ethyl]phenyl]-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to give5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N2-[4-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.83 (d, 1H, J=3.5 Hz), 7.49 (d, 2H, J=8.8 Hz), 7.35(d, 2H, J=8.8 Hz), 7.31 (d, 2H, J=8.8 Hz), 6.82 (d, 2H, J=8.8 Hz), 4.03(t, 2H, J=4.7 Hz), 3.89 (t, 2H, J=4.7 Hz), 3.56 (s, 2H), 1.30 (s, 6H);LCMS: ret. time: 16.86 min.; purity: 96%; MS (m/e): 413 (MH⁺).

7.3.635 (R935160):5-Fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(4-isopropoxyphenyl)-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to give5-fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.12 (s, 1H), 8.92 (s, 1H), 7.98 (d, 1H, J=3.5 Hz),7.59 (d, 2H, J=8.8 Hz), 7.49 (d, 2H, J=9.3 Hz), 6.86 (d, 2H, J=8.8 Hz),6.76 (d, 2H, J=9.3 Hz), 4.82 (t, 1H, J=4.9 Hz), 4.55 (septet, 1H, J=6.4Hz), 3.89 (t, 2H, J=5.3 Hz), 3.67 (app q, 2H, J=5.3 and 4.9 Hz), 1.24(d, 6H, J=6.4 Hz); LCMS: ret. time: 19.56 min.; purity: 100%; MS (m/e):399 (MH⁺).

7.3.636 (R935161):5-Fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N2-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine

In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-[4-(1-ethoxycarbonyl-1-methyl)ethylphenyl]-5-fluoro-N2-(3-methoxycarbonylmethylphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to give5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N2-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.27 (s, 1H), 9.11 (s, 1H), 8.07 (d, 1H, J=3.5 Hz),7.67 (d, 2H, J=8.8 Hz), 7.38-7.24 (m, 4H), 7.06 (t, 1H, J=8.2 Hz), 6.46(dd, 1H, J=8.2 Hz), 4.83 (t, 1H, J=5.3 Hz), 4.66 (t, 1H, J=5.3 Hz), 3.88(t, 2H, J=5.3 Hz), 3.67 (t, 1H, J=5.3 Hz), 3.66 (t, 1H, J=5.3 Hz), 3.38(d, 2H, J=5.3 Hz), 1.20 (s, 6H); LCMS: ret. time: 17.17 min.; purity:96%; MS (m/e): 413 (MH⁺).

7.3.637 (R935168):5-Fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-[4-(1-ethoxycarbonyl-1-methyl)ethylphenyl]-5-fluoro-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to produce5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.21 (s, 1H), 8.93 (s, 1H), 8.00 (d, 1H, J=4.1 Hz),7.62 (d, 2H, J=8.8 Hz), 7.48 (d, 2H, J=8.8 Hz), 7.27 (d, 2H, J=8.8 Hz),6.75 (d, 2H, J=8.8 Hz), 4.65 (t, 1H, J=5.3 Hz), 4.47 (septet, 1H, J=5.8Hz), 3.38 (d, 2H, J=5.3 Hz), 1.22 (d, 6H, J=5.8 Hz), 1.20 (s, 6H); LCMS:ret. time: 22.97 min.; purity: 99%; MS (m/e): 411 (MH⁺).

7.3.638 (R935170):5-Fluoro-N4-[3-(2-hydroxyethoxy)phenyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,5-fluoro-N2-(3-hydroxyphenyl)-N4-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to produce5-fluoro-N4-[3-(2-hydroxyethoxy)phenyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.23 (s, 1H), 9.14 (s, 1H), 9.06 (s, 1H), 8.07 (d,1H, J=4.1 Hz), 7.51 (dd, 1H, J=1.7 and 7.6 Hz), 7.30 (app t, 1H, J=2.3and 1.7 Hz), 7.19 (t, 1H, J=8.2 Hz), 7.13 (br s, 1H), 7.11 (m, 1H), 6.96(t, 1H, J=7.6 Hz), 6.61 (dd, 1H, J=2.3 and 8.2 Hz), 6.28 (dd, 1H, J=2.3Hz and 8.2 Hz), 4.84 (t, 1H, J=5.8 Hz), 3.92 (t, 2H, J=5.2 Hz), 3.68(app qt, 2H, J=5.2 Hz); LCMS: ret. time: 14.71 min.; purity: 96%; MS(m/e): 357 (MH⁺).

7.3.639 (R935171):5-Fluoro-N2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-pyrimidine-2,4-diamine,N4-[4-(1-ethoxycarbonyl-1-methyl)ethyl)phenyl]-5-fluoro-N2-(3-hydoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to give5-fluoro-N2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.24 (s, 1H), 9.13 (s, 1H), 9.01 (s, 1H), 8.04 (d,1H, J=3.5 Hz), 7.68 (d, 2H, J=8.8 Hz), 7.29 (d, 2H, J=8.8 Hz), 7.16 (brs, 1H), 7.07 (m, 1H), 6.94 (t, 1H, 8.8 Hz), 6.30 (m, 1H), 4.64 (t, 1H,J=5.8 Hz), 3.38 (d, 2H, J=5.3 Hz), 1.20 (s, 6H); LCMS: ret. time: 17.36min.; purity: 100%; MS (m/e): 369 (MH⁺).

7.3.640 (R935174):5-Fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(2-hydroxymethylbenzofur-5-yl)-2,4-pyrimidinediamine

In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2-(2-carbomethoxybenzofur-5-yl)-5-fluoro-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to provide5-fluoro-N2[4-(2-hydroxyethoxy)phenyl]-N2-(2-hydroxymethylbenzofur-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.26 (s, 1H), 8.94 (s, 1H), 8.01 (d, 1H, J=4.1 H),7.99 (s, 1H), 7.52-7.45 (m, 4H), 6.72 (d, 2H, J=9.3 Hz), 6.66 (s, 1H),5.46 (t, 1H, J=5.3 Hz), 4.82 (t, 1H, J=5.8 Hz), 4.55 (d, 2H, J=5.8 Hz),3.89 (t, 2H, J=5.3 Hz), 3.67 (app qt, 2H, J=5.3 Hz); LCMS: ret. time:14.97 min.; purity: 91%; MS (m/e): 411 (MH⁺).

7.3.641 (R935176):N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine

In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-(3-methoxycarbonylmethyleneoxypheny)-2,4-pyrimidinediaminewas reduced with DIBALH to provideN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.22 (s, 1H), 8.98 (s, 1H), 8.05 (d, 1H, J=3.5 Hz),7.47 (dd, 1H, J=1.1 and 8.2 Hz), 7.27 (t, 1H, J=1.7 Hz), 7.23 (d, 1H,J=2.3 Hz), 7.18 (t, 1H, J=8.2 Hz), 7.05 (dd, 1H, J=2.3 and 8.8 Hz), 6.68(d, 1H, J=8.2 Hz), 6.61 (dd, 1H, J=1.7 and 8.8 Hz), 4.85 (t, 1H, J=5.3Hz), 4.18-4.14 (m, 4H), 3.91 (t, 2H, J=5.3 Hz), 3.68 (qt, 2H, J=5.3 Hz);LCMS: ret. time: 17.35 min.; purity: 92%; MS (m/e): 399 (MH⁺).

7.3.642 (R935177):5-Fluoro-N2-[4-(2-hydroxy-1,1,dimethylethyl)phenyl]-N4-(2-hydroxymethylbenzofur-5-yl)-2,4-pyrimidinediamine

In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-(2-carbomethoxybenzofur-5-yl)-N2-[4-(1-ethoxycarbonyl-1-methyl)ethylphenyl]-5-fluoro-2,4-pyrimidinediaminewas reduced with DIBALH to produce 5-fluoro-N2-[4-(2-hydroxy-1,1,dimethylethyl)phenyl]-N4-(2-hydroxymethylbenzofur-5-yl)-2,4-pyrimidinediamine.LCMS: ret. time: 18.17 min.; purity: 94%; MS (m/e): 423 (MH⁺).

7.3.643 (R935178):5-Fluoro-N2-[3-(2-hydroxyethyloxy)phenyl]-N4-(2-hydroxymethylbenzofur-5-yl)-2,4-pyrimidinediamine

In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-(2-carbomethoxybenzofur-5-yl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to provide5-fluoro-N2-[3-(2-hydroxyethyloxy)phenyl]-N4-(2-hydroxymethylbenzofur-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.93 (s, 1H), 9.12 (s, 1H), 8.07 (d, 1H, J=3.6 Hz),8.01 (d, 1H, J=2.3 Hz), 7.55-7.46 (m, 2H), 7.29 (br s, 1H), 7.23 (d, 1H,J=8.2 Hz), 7.03 (t, 1H, J=8.2 Hz), 6.68 (s, 1H), 6.44 (dd, 1H, J=2.3 and8.2 Hz), 5.47 (t, 1H, J=5.8 Hz), 4.80 (t, 1H, J=5.3 Hz), 4.55 (d, 2H,J=5.3 Hz), 3.81 (qt, 2H, J=5.3 Hz), 3.63 (qt, 2H, J=5.3 Hz); LCMS: ret.time: 15.41 min.; purity: 88%; MS (m/e): 411 (MH⁺).

7.3.644 (R935181):N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine

In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-(3,5-dimethoxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidineaminewas reduced with DIBALH to giveN4-(3,5-dimethoxyphenyl)-5-fluoro-N2-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine:¹H NMR (DMSO-d6): δ 9.24 (s, 1H), 9.18 (s, 1H), 8.11 (d, 1H, J=3.5 Hz),7.31-7.26 (m, 2H), 7.05 (d, 1H, J=8.2 Hz), 6.99 (d, 1H, J=2.3 Hz), 6.43(dd, 1H, J=2.3 Hz, 8.2 Hz), 6.20 (t, 1H, J=2.3 Hz), 4.80 (t, 1H, J=5.8Hz), 3.83 (t, 2H, J=5.3 Hz), 3.67 (s, 6H), 3.66-3.60 (m, 2H); LCMS: ret.time: 18.78 min.; purity: 95%; MS (m/e): 400 (MH⁺).

7.3.645 (R935183):5-Fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,5-fluoro-N2-[4-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBAL-H to provide5-fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine.H NMR (DMSO-d6): δ 9.15 (s, 1H), 8.97 (s, 1H), 8.00 (d, 1H, J=3.5 Hz),7.49 (d, 2H; J=8.8 Hz), 7.40-7.31 (m 2H), 6.88 (d, 1H, J=8.8 Hz), 6.80(d, 2H, J=8.8 Hz), 4.82 (t, 1H, J=5.3 Hz), 4.12-4.04 (m 4H), 3.90 (t,2H, J=5.2 Hz), 3.70-3.65 (app qt, 2H, J=5.3 Hz), 2.07 (q, 2H, J=5.3 Hz);LCMS: ret. time: 17.05 min.; purity: 96%; MS (m/e): 413 (MH⁺).

7.3.646 (R935186):5-Fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine

In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,5-fluoro-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to provide5-fluoro-N2-[3-(2-hydroxyethoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.21 (s, 1H), 9.14 (s, 1H), 8.07 (d, 1H, J=3.5 Hz),7.42-7.36 (m, 2H), 7.29-7.24 (m, 2H), 7.07 (t, 1H, J=8.2 Hz), 6.90 (d,1H, J=8.8 Hz), 6.45 (dd, 1H, J=1.7 and 8.3 Hz), 4.82 (t, 1H, J=5.3 Hz),4.12-4.04 (app q, 2H, J=5.3 Hz), 3.86 (t, 2H, J=5.3 Hz), 3.67 (app qt,2H, J=5.3 Hz), 2.07 (q, 2H, J=5.3 Hz); LCMS: ret. time:17.95 min.;purity: 96%; MS (m/e): 413 (MH⁺).

7.3.647N4-(4-tert-Butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine(R926720)

The reaction ofN2-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamineand lithium hydroxide (LiOH) in THF:H₂O at room temperature gaveN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.01 (bs, 1H), 9.69 (bs, 1H), 8.13 (d, 1H, J=4.8Hz), 7.57 (d, 2H, J=8.7 Hz), 7.50 (s, 1H), 7.35 (d, 2H, J=8.1 Hz), 7.13(d, 1H, J=8.7 Hz), 6.75 (d, 1H, J=9.0 Hz), 5.21 (dd, 1H, J=6.3 and 10.5Hz), 3.49 (dd, 1H, J=10.5 and 16.5 Hz), 3.17 (dd, 1H, J=6.6 and 16.5Hz), 1.27 (s, 9H); LCMS: ret. time: 22.53 min.; purity: 93%; MS (m/e):423 (MH⁺).

7.3.648N4-(4-tert-Butylphenyl)-N2-(3-carboxymethyleneoxyphenyl)-5-fluor-2,4-pyrimidinediamine(R926726)

In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,N4-(4-tert-butylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand lithium hydroxide were reacted to yieldN4-(4-tert-butylphenyl)-5-fluoro-N2-(3-carboxymethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 12.88 (bs, 1H), 9.29 (s, 1H), 9.16 (s, 1H), 8.07 (d,1H, J=3.3 Hz), 7.68 (d, 2H, J=8.7 Hz), 7.35-7.31 (m, 3H), 7.26 (d, 1H,J=8.4 Hz), 7.06 (t, 1H, J=8.4 Hz), 6.41 (dd, 1H, J=2.4 and 8.4 Hz), 4.54(s, 2H), 1.27 (s, 9H); ¹⁹F NMR (DMSO-d6): −46463; LCMS: ret. time: 22.94min.; purity: 97%; MS (m/e): 411 (MH⁺).

7.3.6495-Fluoro-N2-[3-(carboxymethyleneoxy)phenyl]-N4-[4-(isopropoxy)phenyl]-2,4-pyrimidinediamine(R926731)

In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamineand lithium hydroxide were reacted to yield5-fluoro-N2-(3-carboxymethyleneoxyphenyl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 6.19 (bs, 1H), 9.01 (s, 1H), 8.02 (d, 1H, J=3.9 Hz),7.63 (d, 2H, J=9.3 Hz), 7.19-7.14 (m, 2H), 6.96 (t, 1H, J=8.7 Hz), 6.87(d, 2H, J=9.6 Hz), 6.28 (dd, 1H, J=2.45 and 9.0 Hz), 4.56 (2q, 1H, J=6.6Hz), 3.94 (s, 2H), 1.24 (d, 6H, J=6.6 Hz); LCMS: ret. time: 20.13 min.;purity: 100%; MS (m/e): 413 (MH⁺).

7.3.650N2,N4-Bis(4-carboxymethyleneoxy)phenyl-5-fluoro-2,4-pyrimidinediamine(R926560)

In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,thehydrolysis ofN2,N4-bis(4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith LiOH gaveN2,N4-bis(4-carboxymethyleneoxy)phenyl-5-fluoro-2,4-pyrimidinediamine ¹HNMR (CD₃OD): δ 7.86 (bs, 1H), 7.55 (d, 2H, J=9.0 Hz), 7.32 (bd, 2H,J=9.3 Hz), 6.95 (m, 4H), 4.66 (s, 2H), ¹⁹F NMR (CDCl₃): −21852; LCMS:ret. time: 15.16 min.; purity: 77%; MS (m/e): 429 (MH⁺).

7.3.651N2-(3-Carboxymethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926483)

In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,thereaction ofN2-(3-ethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith LiOH gaveN2-(3-carboxymethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 12.90 (s, 1H), 9.20 (s, 2H), 8.05 (d, 1H, J=1.2 Hz),7.32-7.21 (m, 3H), 7.08 (t, 1H, J=8.1 Hz), 6.80 (d, 1H, J=8.4 Hz), 6.40(dd, 1H, J=1.8 and 8.2 Hz), 4.53 (s, 2H), 4.20 (s, 4H); LCMS: ret. time:18.26 min.; purity: 100%; MS (m/e): 413 (MH⁺).

7.3.652N2-(3-Carboxymethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945126)

In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,the reaction of5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-(methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewith LiOH gaveN2-(3-carboxymethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine¹H NMR (DMSO-d6): δ 4.55 (s, 2H), 6.43 (dd, J=2.1, 8.1 Hz, 1H), 6.48(dd, J=2.1 and 7.2 Hz, 1H), 7.06-7.13 (m, 3H), 7.28-7.34 (m, 3H), 8.09(d, J=3.6 Hz, 1H), 9.22 (br, 1H), 9.28 (br, 1H), 9.34 (br, 1H); ¹⁹F NMR(282 MHz, DMSO-d6): δ −163.85; LCMS: ret. time: 15.88 min.; purity:100%; MS (m/e): 370.63 (MH⁺).

7.3.653N2-(4-Carboxymethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926238)

In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,the reaction ofN2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith LiOH gaveN2-(carboxymethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 8.16 (d, 1H, J=4.8 Hz), 7.37 (bd, 2H, J=9 Hz), 7.259d, 1H, J=3 Hz), 7.08 (m, 1H), 6.83 (m, 3H), 4.64 (s, 2H), 4.23 (s, 4H);LCMS: ret. time: 19.15 min.; purity: 100%; MS (m/e): 413 (MH⁺).

7.3.654N2-(4-Carboxymethyleneoxyphenyl)-5-Fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926564)

In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,5-fluoro-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineupon treatment with LiOH gave5-fluoro-N2-(4-carboxymethyleneoxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.89 (d, 1H, J=5.1 Hz), 7.34 (dd, 2H, J=2.1 and 9.3Hz), 7.19-7.08 (m, 2H), 6.98 (dd, 2H, J=2.4 and 8.4 Hz), 6.69 (m, 1H),4.68 (s, 2H); ¹⁹F NMR (CD₃OD): −21860; LCMS: ret. time: 15.69 min.;purity: 99%; MS (m/e): 371 (MH⁺).

7.3.655N2-(2-Carboxybenzofuran-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926478)

In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-4-pyrimidinediamineupon LiOH treatment gaveN2-(2-carboxybenzofuran-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.97 (bd, 2H), 7.60-7.44 (m, 4H), 7.20-7.05 (m, 3H),6.69 (bd, 1H); ¹⁹F NMR (CD₃OD): −21844; LCMS: ret. time: 16.77 min.;purity: 100%; MS (m/e): 381 (MH⁺).

7.3.656N2-(2-Carboxyindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926479)

In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,N2-(2-ethoxycarbonylindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineupon LiOH treatment gaveN2-(2-carboxyindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.83 (m, 1H), 7.73 (s, 1H), 7.50 (bd, 1H, J=8.7 Hz),7.30-7.11 (m, 5H), 6.68 (bd, 1H); LCMS: ret. time: 16.50 min.; purity:97%; MS (m/e): 380 (MH⁺).

7.3.657N4-(4-tert-Butylphenyl)-N2-(2-carboxybenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine(R926481)

In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,LiOH treatment withN4-(4-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediaminegaveN4-(4-tert-butylphenyl)-N2-(2-carboxybenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 9.3 (bd, 2H), 8.25 (s, 1H), 8.10 (s, 1H), 7.65-7.30(m, 5H), 1.25 (s, 9H); ¹⁹F NMR (CD₃OD): −21844; LCMS: ret. time: 23.32min.; purity: 100%; MS (m/e): 421 (MH⁺).

7.3.658N4-(3-tert-Butylphenyl)-N2-[3-carboxymethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamineR940280

In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,N4-(3-tert-butylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewas reacted with LiOH to giveN4-(3-tert-butylphenyl)-N2-(3-carboxymethyleneoxyphenyl)-5-fluoro2,4-pyrimidinediamine. LCMS: ret. time: 23.61 min.; purity: 99%; MS(m/e): 410 (M⁺), 412 (MH⁺); ¹H NMR (DMSO-d6): δ 9.45 (1H, s), 9.33 (1H,s), 8.21 (1H, d, J=3.9 Hz), 7.98 (1H, d, J=6.6 Hz), 7.60 (1H, t, J=2Hz), 7.44-7.34 (3H, m), 7.24-7.15 (2H, m), 6.54 (1H, d, J=7.8 Hz), 4.68(2H, s), 1.36 (9H, s).

7.3.659N2-(3-Carboxymethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950190)

The reaction ofN2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(0.1 g) and LiOH (10 equivalents) in MeOH:water (1:1, v/v) for 1 h atroom temperature followed by treatment with aqueous HCl gave the solid.The resulting solid was filtered, washed with water and dried to giveN2-(3-carboxymethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 18.23 min.; purity: 87.6%; MS (m/e): 412.01 (MH⁺).

7.3.660N2-(Carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethyloxy)phenyl]-2,4-pyrimidinediamine(R950230)

In a manner similar to the preparation ofN2-(3-carboxymethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine,the hydrolysis ofN2-(ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylenoxy)phenyl]-2,4-pyrimidinediaminewith LiOH gaveN2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethyloxy)phenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 12.15 min.; purity: 78.3%; MS (m/e): 413.01 (MH⁺).

7.3.6615-Fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950231)

A mixture ofN2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine(10 mg), 2-aminoethanol (10 equiv.) and PyBroP (2 equiv.) was stirred in0.5 ml DMF for 24 hours at room temperature. The mixture was dilutedwith water, extracted with EtOAc and the organic phase was dried overMgSO₄. The solvent was removed under reduced pressure and the residuewas subjected to column chromatography on silica gel (CHCl₃:Acetone,2:1) to give5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine. LCMS: ret. time: 12.98 min.; purity:92.6%; MS (m/e): 455.97 (MH⁺).

7.3.662 N2-[3-(N-2-Aminoethylamino)carbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylenoxy)phenyl]-2,4-pyrimidinediamine(R950232)

In like manner to the preparation ofN4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine,N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamineand 1,2-ethylenediamine were reacted to affordN2-[3-(N-2-aminoethylamino)carbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylenoxy)phenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 11.31 min.; purity: 93.6%; MS (m/e): 454.94 (MH⁺).

7.3.6635-Fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-(N-methylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950233)

In like manner to the preparation ofN4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine,N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamineand methylamine were reacted to give5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-(N-methylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 14.93 min.; purity: 92.9%; MS (m/e): 426.27 (MH⁺).

7.3.6645-Fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-methylamino)ethylamino]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950234)

In like manner to the preparation ofN4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine,N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamineand N-methylethylenediamine were reacted to give5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-methylamino)ethylamino]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 11.39 min.; purity: 97.7%; MS (m/e): 468.96 (MH⁺).

7.3.665 N2-[3-[N-(2-N-Benzylamino)ethylamino]carbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine(R950235)

In like manner to the preparation ofN4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine,N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamineand N-benzylethylenediamine were reacted to giveN2-[3-[N-(2-N-benzylamino)ethylamino]carbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 14.39 min.; purity: 97.3%; MS (m/e): 545.01 (MH⁺).

7.3.6665-Fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-(N-morpholino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950236)

In like manner to the preparation ofN4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine,N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamineand morpholine were reacted to afford5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-(N-morpholino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 15.24 min.; purity: 94.6xx %; MS (m/e): 482.40 (MH⁺).

7.3.667 N2-[3-(3-N,N-Dimethylaminopropyl)aminocarbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine(R950237)

In like manner to the preparation ofN4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine,N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamineand N,N-dimethylpropanediamine were reacted to giveN2-[3-(3-N,N-Dimethylaminopropyl)aminocarbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 13.33 min.; purity: 91.4%; MS (m/e): 497.47 (MH⁺).

7.3.668 N2-[3-[N-(2,3-Dihydroxypropyl)amino]carbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine(R950238)

In like manner to the preparation ofN4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine,N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamineand 1-amino-2,3-propanediol were reacted to giveN2-[3-[N-(2,3-dihydroxypropyl)amino]carbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 12.86 min.; purity: 90.0%; MS (m/e): 486.40 (MH⁺).

7.3.6695-Fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950239)

In like manner to the preparation ofN4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine,N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamineand 4-(2-aminoethyl)morpholine were reacted to give5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine. LCMS: ret. time:13.52 min.; purity: 92.4%; MS (m/e): 525.47 (MH⁺).

7.3.670 2,4-Bis[N-(L)-tyrosine methyl ester]-5-ethoxycarbonylpyrimidine(R926514) and 5-Ethoxycarbonyl-2-methoxy-4-[N-(L)-tyrosine methylester]pyrimidine (R926513)

A mixture of tyrosine methyl ester (58 mg, 0.3 mmol),2,4-dichloro-5-ethoxycarbonylpyrimidine (44 mg, 0.1 mmol) in MeOH (2 mL)was heated in a sealed tube at 100° C. for a period of overnight,diluted with H₂O (20 mL), acidified with 2N HCl and extracted with ethylacetate (3×25 mL). The solvent was evaporated and the residue waspurified by preparative TLC using 30% EtOAc/Hexanes to obtain a mixtureof 2,4-bis[N-(L)-tyrosine methyl ester]-5-ethoxycarbonylpyrimidine(R926514). ¹H NMR (CDCl₃): δ 8.60 (1H, J=6.6 Hz), 8.36 (s, 1H), 7.05 (d,2H, J=8.7 Hz), 6.84 (d, 2H, J=8.1 Hz), 6.74 (d, 2H, J=9 Hz), 6.54 (d,2H, J=9 Hz), 4.82 (t, 2H, J=6 Hz), 4.25 (q, 2H, J=6.3 Hz), 3.73 (s, 3H),3.72 (s, 3H), 3.06 (m, 4H), 1.31 (t, 3H, J=7.2 Hz) and5-ethoxycarbonyl-2-methoxy-4-[N-(L)-tyrosine methyl ester]pyrimidine(R926513): ¹H NMR (CDCl₃): δ 8.78 (s, 1H), 8.65 (d, 1H, J=6.9 Hz), 7.02(dd, 2H, J=2.1 and 6.3 Hz), 6.77 (dd, 2H, J=2.4 and 6.6 Hz), 4.93 (q,1H, J=1.5 and 6.9 Hz), 4.30 (q, 2H, J=8.1 Hz), 3.90 (s, 3H), 3.70 (s,3H), 3.17 (dd, 1H, J=5.4 Hz), 3.06 (dd, 1H, J=7.5 and 7.8 Hz), 1.33 (t,3H, J=6.9 Hz); LCMS: ret. time: 22.58 min.; purity: 99%; MS (m/e): 376(M⁺).

7.3.671N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926252)

In like manner to the preparation of N2,N4-bis[N-(L)-tyrosine methylester]-5-ethoxycarbonylpyrimidine, the reaction of2,4-dichloro-5-ethoxycarbonylpyrimidine with 3,4-ethylenedioxyanilinegaveN2,N4-bis(3,4-ethylenedioxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.01 (s, 1H), 9.65 (bs, 1H), 8.62 (s, 1H), 7.18(bs, 2H), 7.04 (dd, 1H, J=1.8 and 8.7 Hz), 6.93 (d, 1H, J=7.5 Hz), 6.76(d, 1H, J=8.7 Hz), 6.65 (d, 1H, J=8.7 Hz), 4.28 (q, 2H, J=6.9 Hz), 1.31(t, 3H, J=7.2 Hz); LCMS: ret. time: 27.25 min.; purity: 100%; MS (m/e):451 (MH⁺).

7.3.672N2,N4-Bis(4-methoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926253)

In like manner to the preparation of N2,N4-bis[N-(L)-tyrosine methylester]-5-ethoxycarbonylpyrimidine, the reaction of2,4-dichloro-5-ethoxycarbonylpyrimidine with ethyl 4-aminophenoxyacetategaveN2,N4-bis(4-methoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926253). ¹H NMR (CD₃OD): δ 8.60 (bs, 1H), 7.4 (bs, 1H), 7.33 (d, 4H,J=9 Hz), 6.94 (bd, 4H), 4.76 (s, 2H), 4.75 (s, 2H), 4.44 (q, 2H, J=6.9Hz), 3.79 (s, 3H), 1.40 (t, 3H, J=6.9 Hz); LCMS: ret. time: 25.83 min.;purity: 89%; MS (m/e): 511 (MH⁺).

7.3.673 2,4-Bis[N-(L)-phenylalaninyl ethylester]-5-ethoxycarbonylpyrimidine (R926526)

In like manner to the preparation of N2,N4-bis[N-(L)-tyrosine methylester]-5-ethoxycarbonylpyrimidine, the reaction of2,4-dichloro-5-ethoxycarbonylpyrimidine with ethyl (L)-phenylalanineethyl ester in MeOH or EtOAc gave 2,4-bis[N-(L)-phenylalanine ethylester]-5-ethoxycarbonylpyrimidine. ¹H NMR (CDCl₃): δ 8.55 (d, 1H, J=7.2Hz), 8.51 (s, 1H), 7.35-7.10 (m, 10H), 5.88 (d, 1H, J=J=6 Hz), 4.88(ddd, 1H, J=6.3 Hz), 4.80 (ddd, 1H, J=6.3 Hz), 4.23 (q, 2H, J=7.2 Hz),4.12 (q, 4H, J=7.2 Hz), 3.65 (t, 2H, J=6 Hz), 3.56 (t, 2H, J=6.0 Hz),1.30 (t, 2H, J=6 Hz), 1.30 (t, 3H, J=7.2 Hz), 1.20 (m, 6H); LCMS: ret.time: 32.22 min.; purity: 89%; MS (m/e): 535 (MH⁺).

7.3.674 2,4-Bis[N-(L)-valinyl ethyl ester]-5-ethoxycarbonylpyrimidine(R926527)

In like manner to the preparation of N2,N4-bis[N-(L)-tyrosine methylester]-5-ethoxycarbonylpyrimidine, the reaction of2,4-dichloro-5-ethoxycarbonylpyrimidine with ethyl (L)-valine ethylester in MeOH or EtOAc gave 2,4-bis[N-(L)-valinyl ethylester]-5-ethoxycarbonylpyrimidine. ¹H NMR (CDCl₃): δ 8.59 (d, 1H, J=7.8Hz), 8.56 (s, 1H), 5.69 (d, 1H, J=8.7 Hz), 4.62 (m, 1H), 4.51 (m, 1H),4.25 (q, 2H, J=7.5 Hz), 4.20 (m, 4H), 2.20 (m, 2H), 1.34 (t, 3H, J=7.8Hz), 1.27 (t, 6H, J=7.5 Hz), 1.00 (m, 12H); LCMS: ret. time: 29.27 min.;purity: 97%; MS (m/e): 439 (MH⁺).

7.3.675 5-Ethoxycarbonyl-N2-(3-hydroxyphenyl)-4-[N-(L)-phenylalanineethyl ester]-2-pyrimidineamine (R926528)

The reaction of2-chloro-N4-(3-hydroxyphenyl)-5-ethoxycarbonylpyrimidineamine with 3equivalents of (L)-N-phenylalanine ethyl ester in methanol at 80-100° C.for 24 h followed by dilution with water and acidification with 2N HClhave the acidic solution. The resulting solution was extracted withEtOAc and the residue was purified by silics gel column chromatographyto afford 4-[N-(L)-phenylalanine ethylester]-N2-(3-hydroxyphenyl)-5-ethoxycarbonyl-2-pyrimidineamine. ¹H NMR(CDCl₃): δ 9.4 (bs, 1H), 9.13 (d, 1H, J=6 Hz), 8.45 (bs, 1H), 7.59 (s,1H), 7.34-7.25 (m, 5H), 7.15 (t, 1H, J=8.1 Hz), 6.73 (bd, 1H, J=7.5 Hz),6.67 (dd, 1H, J=1.8 and 7.8 Hz), 4.86 (dt, 1H, J=3 and 5.1 Hz), 4.32 (q,2H, J=6.3 Hz), 4.19 (q, 2H, J=7.2 Hz), 3.30 (dd, 1H, J=4.8 and 8.7 Hz),3.18 (dd, 1H, J=5.1 and 8.7 Hz), 1.36 (t, 3H, J=6.9 Hz), 1.65 (t, 3H,J=7.2 Hz); LCMS: ret. time: 27.49 min.; purity: 91%; MS (m/e): 451(MH⁺).

7.3.676 N2-(3,4-Ethylenedioxyphenyl)-5-ethoxycarbonyl-4-[N-(L)-phenylglycinyl ethyl ester)-2-pyrimidineamine (R926536)

In like manner to the preparation of 4-[N-(L)-phenylalanine ethylester]-N2-(3-hydroxyphenyl)-5-ethoxycarbonyl-2-pyrimidineamine, thereaction of 2-chloro-5-ethoxycarbonyl-4-[N-(L)-phenyl glycinyl ethylester)pyrimidine with 3,4-ethylenedioxyaniline in MeOH or EtOAc gaveN2-(3,4-ethylenedioxyphenyl)-5-ethoxycarbonyl-4-[N-(L)-phenyl glycinylethyl ester]-2-pyrimidineamine. ¹H NMR (CDCl₃): δ 9.15 (s, 1H), 8.9 (s,1H), 8.61 (s, 1H), 7.48 (m, 2H), 7.38 (m, 3H), 7.16 (bs, 1H), 6.80 (m,2H0, 5.75 (d, 1H), 4.24 (m, 6H), 3.66 (s, 3H), 1.35 (t, 3H); LCMS: ret.time: 28.16 min.; purity: 85%; MS (m/e): 465 (MH⁺).

7.3.677N4-(4-tert-Butoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R926579)

In like manner to the preparation of 4-[N-(L)-phenylalanine ethylester]-N2-(3-hydroxyphenyl)-5-ethoxycarbonyl-2-pyrimidineamine, thereaction ofN4-(4-tert-butoxycarbonylmethyleneoxyphenyl)-2-chloro-5-ethoxycarbonyl-4-pyrimidineaminewith methyl 4-aminophenoxyacetate gaveN4-(4-tert-butoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 10.17 (s, 1H), 8.73 (s, 1H), 8.45 (bs, 1H), 7.49 (d,2H, J=8.7 Hz), 7.43 (d, 2H, J=8.7 Hz), 7.33 (bs, 1H), 6.87 (d, 2H, J=6Hz), 6.84 (d, 2H, J=5.7 Hz), 4.63 (s, 2H), 4.53 (s, 2H), 4.33 (q, 2H,J=6.9 Hz), 3.81 (s, 3H), 1.49 (s, 9H), 1.39 (t, 3H, J=7.5 Hz); LCMS:ret. time: 27.93 min.; purity: 96%; MS (m/e): 553 (MH⁺).

7.3.678N4-(4-tert-Butoxycarbonylmethyleneoxyphenyl)-N2-(4-methoxycarbonylmethyleneoxyphenyl)-5-methoxycarbonyl-2,4-pyrimidinediamine(R926580)

In like manner to the preparation of 4-[N-(L)-phenylalanine ethylester]-N2-(3-hydroxyphenyl)-5-ethoxycarbonyl-2-pyrimidineamine, thereaction ofN4-(4-tert-butoxycarbonylmethyleneoxyphenyl)-2-chloro-5-ethoxycarbonyl-4-pyrimidineaminewith methyl 4-aminophenoxyacetate gaveN4-(4-tert-butoxycarbonylmethyleneoxyphenyl)-5-methoxycarbonyl-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.5-methyl ester was obtained due to the cross esterification reaction inMeOH. ¹H NMR (CDCl₃): δ 10.13 (s, 1H), 8.73 (s, 1H), 8.45 (bs, 1H), 7.49(d, 2H, J=8.7 Hz), 7.43 (d, 2H, J=8.7 Hz), 7.33 (bs, 1H), 6.87 (m, 4H),4.63 (s, 2H), 4.53 (s, 2H), 4.33 (q, 2H, J=6.9 Hz), 3.88 (s, 3H), 3.81(s, 3H), 1.49 (s, 9H); LCMS: ret. time: 27.43 min.; purity: 100%; MS(m/e): 539 (MH⁺).

7.3.679N4-(4-Carboxymethyleneoxyphenyl)-5-ethoxycarbonyl-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R926583)

The treatment ofN4-(4-tert-butoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewith trifluoroacetic acid in THF:H₂O at room temperature affordedN4-(4-carboxymethyleneoxyphenyl)-5-ethoxycarbonyl-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.03 (s, 1H), 8.65 (s, 1H), 7.49 (bd, 4H, J=8.7Hz), 6.89 (d, 2H, J=9.3 Hz), 6.81 (d, 2H, J=8.1 Hz), 4.70 (s, 2H), 4.65(s, 2H), 4.33 (q, 2H, J=6.9 Hz), 3.81 (s, 3H), 1.49 (s, 9H), 1.39 (t,3H, J=7.5 Hz); LCMS: ret. time: 22.28 min.; purity: 73%; MS (m/e): 497(MH⁺).

7.3.680N2-(4-Carboxymethyleneoxyphenyl)-5-ethoxycarbonyl-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R926584)

The treatment ofN2-(4-tert-butoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewith trifluoroacetic acid in THF:H₂O at room temperature affordedN2-(4-carboxymethyleneoxyphenyl)-5-ethoxycarbonyl-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.H NMR (DMSO-d6): δ 10.01 (s, 1H), 8.64 (s, 1H), 7.45 (bd, 4H, J=7.2 Hz),6.90 (d, 2H, J=8.7 Hz), 6.75 (d, 2H, J=8.4 Hz), 4.80 (s, 2H), 4.38 (s,2H), 4.26 (q, 2H, J=7.2 Hz), 3.70 (s, 3H), 1.30 (t, 3H, J=7.2 Hz); LCMS:ret. time: 22.37 min.; purity: 100%; MS (m/e): 497 (MH⁺).

7.3.6815-Carboxy-N2-(3-hydroxyphenyl)-N4-[N-(L)-phenylglycine)-2-pyrimidineamine(R926535)

The LiOH hydrolysis ofN2-(3-hydroxyphenyl)-5-ethoxycarbonyl-4-[N-(L)-phenyl glycine ethylester]-2-pyrimidineamine affored5-carboxy-N2-(3-hydroxyphenyl)-N4-[N-(L)-phenylglycine)-2-pyrimidineamine.¹H NMR (CD₃OD): δ 8.89 (s, 1H), 8.50 (s, 1H), 7.43 (m, 2H), 7.33 (m,3H), 7.14 (m, 2H), 6.98 (m, 2H), 6.62 (m, 1H), 5.71 (s, 1H); LCMS: ret.time: 17.75 min.; purity: 73%; MS (m/e): 382 (MH⁺).

7.3.6825-Amino-6-ethoxycarbonyl-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine(R925856)

A suspension of6-ethoxycarbonyl-N2,N4-bis(3-hydroxyphenyl)-5-nitro-2,4-pyrimidinediamineand 10% Pd/C (10% by weight) in ethanol was prepared and reacted in aParr bottle under hydrogen gas (20 PSI) for 1 h. The reaction mixturewas filtered through Celite. Purification by column chromatography gave5-amino-6-ethoxycarbonyl-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.30 (bs, 1H), 7.18-7.10 (m, 3H), 7.00 (t, 2H, J=8.1Hz), 6.59-6.54 (m, 1H), 6.33 (dd, 1H, J=2.1 and 11.1 Hz), 4.39 (q, 2H,J=6.9 Hz), 1.43 (t, 3H, J=6.9 Hz); LCMS: ret. time: 19.24 min.; purity:100%; MS (m/e): 382 (MH⁺).

7.3.6835-Amino-6-ethoxycarbonyl-N2,N4-bis(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine(R925857)

In a manner similar to the preparation of5-amino-6-ethoxycarbonyl-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine,6-ethoxycarbonyl-N2,N4-bis(3,4-ethylenedioxyphenyl)-5-nitro-2,4-pyrimidinediamine,hydrogen, and 10% Pd/C were reacted to yield5-amino-6-ethoxycarbonyl-N2,N4-bis(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.16 (d, 1H, J=2.4 Hz), 7.07 (d, 1H, J=2.4 Hz), 7.04(dd, 1H, J=2.4 and 9.0 Hz), 6.84-6.79 (m, 2H), 6.70 (d, 1H, J=9.0), 4.43(q, 2H, J=7.8 Hz), 4.25 (s, 4H), 4.21 (bs, 4H), 1.43 (t, 3H, J=7.8 Hz);LCMS: ret. time: 23.70 min.; purity: 100%; MS (m/e): 466 (MH⁺).

7.3.6845-Amino-N2,N4-bis(ethoxycarbonylmethyl)-6-ethoxycarbonyl-2,4-pyrimidinediamine(R925865)

In a manner similar to the preparation of5-amino-6-ethoxycarbonyl-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine,6-ethoxycarbonyl-N2,N4-bis(ethoxycarbonylmethyl)-5-nitro-2,4-pyrimidinediamine,hydrogen, and 10% Pd/C were reacted to yield5-amino-N2,N4-bis(ethoxycarbonylmethyl)-6-ethoxycarbonyl-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 6.25 (bs, 2H), 4.38 (q, 2H, J=6.9 Hz), 4.23-4.14 (m,6H), 4.05 (bs, 2H), 1.39 (t, 3H, J=6.9 Hz), 1.30-1.22 (m, 6H); LCMS:ret. time: 17.67 min.; purity: 95%; MS (m/e): 370 (MH⁺).

7.3.6855-Amino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-2,4-pyrimidinediamine(R926567)

Hydrogenation ofN2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamineusing Pd/C in MeOH at 40 PSI gave5-amino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.47 (d, 2H, J=8.7 Hz), 7.41 (d, 2H, J=8.7 Hz), 6.88(d, 2H, J=8.1 Hz), 6.81 (d, 2H, J=8.7 Hz), 4.63 (s, 2H), 4.59 (s, 2H),4.41 (q, 2H, J=7.5 Hz), 4.29 (m, 4H), 1.44 (t, 3H), 1.31 (m, 6H); LCMS:ret. time: 26.15 min.; purity: 97%; MS (m/e): 554 (MH⁺).

7.3.686N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(phenylaminocarbonylamino)-2,4-pyrimidinediamine(R926571)

A dry reaction flask equipped with a rubber septum and a N₂ inlet wascharged with5-amino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-2,4-pyrimidinediamine,equimolar amount of pyridine and phenyl isocyanate at room temperature.The reaction was allowed to stirred at room temperature for overnightand the resulting reaction was poured over n-hexane to precipitate thedesired product,N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(phenylaminocarbonylamino)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.92 (s, 1H), 7.47 (s, 1H), 7.35 (bt, 5H, J=8.4 Hz),7.25 (bt, 2H, J=7.5 Hz), 7.03 (m, 2H), 6.81 (d, 2H, J=8.7 Hz), 6.76 (d,2H, J=8.7 Hz), 4.60 (s, 2H), 4.58 (s, 2H), 4.29 (m, 6H), 1.45 (m, 9H);LCMS: ret. time: 27.75 min.; purity: 91%; MS (m/e): 673 (MH⁺).

7.3.6875-Allylaminocarbonylamino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl)-2,4-pyrimidinediamine(R926585)

In like manner to the preparation of N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(phenylaminocarbonylamino)-2,4-pyrimidinediamine,the reaction of5-amino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-2,4-pyrimidinediaminewith allyl isocyanate gave5-allylaminocarbonylamino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl)-2,4-pyrimidinediamine.LCMS: ret. time: 25.60 min.; purity: 91%; MS (m/e): 637 (MH⁺).

7.3.688N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(ethoxycarbonylaminocarbonylamino)-2,4-5-pyrimidinetriamine(R926586)

In like manner to the preparation of N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(phenylaminocarbonylamino)-2,4-pyrimidinediamine,the reaction of5-amino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-2,4-pyrimidinediaminewith ethoxycarbonyl isocyanate gaveN2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(ethoxycarbonylaminocarbonylamino)-2,4-pyrimidinediamine.LCMS: ret. time: 26.79 min.; purity: 88%; MS (m/e): 669 (MH⁺).

7.3.689N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(ethoxycarbonylmethyleneaminocarbonylamino)-2,4-pyrimidinediamine (R926587)

In like manner to the preparation of N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(phenylaminocarbonylamino)-2,4-pyrimidinediamine,the reaction of5-amino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-2,4-pyrimidinediaminewith ethylacetyl isocyanate gaveN2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(ethoxycarbonylmethyleneaminocarbonylamino)-2,4-pyrimidinediamine.LCMS: ret. time: 25.76 min.; purity: 96%; MS (m/e): 683 (MH⁺).

7.3.690N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(cyclopentylaminocarbonylamino)-2,4-pyrimidinediamine(R926588)

In like manner to the preparation of N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(phenylaminocarbonylamino)-2,4-pyrimidinediamine,the reaction of5-amino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-2,4-pyrimidinediaminewith cyclopentyl isocyanate gaveN2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(cyclopentylaminoacrbonylamino)-2,4-pyrimidinediamine.LCMS: ret. time: 27.36 min.; purity: 83%; MS (m/e): 665 (MH⁺).

7.3.691N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(chloroacetylaminocarbonylamino)-2,4-pyrimidinediamine(R926589)

In like manner to the preparation of N2,N4-bis(ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(N-phenylformyl-amino)-2,4-pyrimidinediamine,the reaction ofN5-amino-N2,N4-bis(ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-2,4-pyrimidinediaminewith chloroacetylformyl isocyanate gaveN2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(chloroacetylaminocarbonylamino)-2,4-pyrimidinediamine. LCMS: ret. time: 26.60 min.;purity: 100%; MS (m/e): 580 (MH⁺).

7.3.692 (R920669):N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-trifluoro-2,4-pyridinediamine

A mixture of 2,4-dichloro-5-trifluoromethylpyrimidine (416 mg, 1.9mmol), 3,4-ethylenedioxyaniline (0.5 mL, 4.1 mmol), and concentrated HCl(0.1 mL) in 1:9 acetone/H₂O (10 mL) was heated to reflux. After 1 h, thereaction was complete as determined by TLC. The mixture was cooled toroom temperature and EtOAc (30 mL) was added. The organic layer waswashed with 2 N HCl (2×15 mL), water (15 mL), and dried (Na₂SO₄). Theorganic layer was filtered through a silica gel pad, washing the filtercake with EtOAc, and concentrated. The material was purified bychromatography (silica gel, 95:5 dichloromethane/ethyl acetate) toaffordN2,N4-bis(3,4-ethylenedioxyphenyl)-5-trifluoro-2,4-pyridinediamine (380mg, 44%): R_(f) 0.27 (silica gel, 9.5:0.5 dichloromethane/ethylacetate); mp 141-143° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.25 (s, 1H), 7.07(m, 2H), 6.99 (bs, 1H), 6.93-6.84 (m, 3H), 6.77-6.74 (m, 1H), 6.67 (bs,1H), 4.29-4.24 (m, 8H); ¹³C NMR (75 MHz, CDCl₃) δ 161.2, 157.9, 155.8,143.7, 132.6, 131.1, 117.5, 117.3, 114.4, 113.2, 110.3, 64.7, 64.5; IR(ATR) 3446 cm⁻¹; ESI MS m/z 447 [C₂₁H₁₇F₃N₄O₄+H]⁺; HPLC (Method C)>99%(AUC), t_(R)=8.5 min. Anal. Calcd for C₂₁H₁₇F₃N₄O₄: C, 56.50; H, 3.84;N, 12.55. Found: C, 56.46; H, 4.41; N, 12.57.

7.3.693 (R920668):N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-pyridyl)-2,4-pyrimidinediamine

A mixture of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (280mg, 1 mmol), 3-aminopyridine (113 mg, 1.2 mmol), sodium t-butoxide (134mg, 1.4 mmol), binap (38 mg, 0.06 mmol), and palladium(II)acetate (14mg, 0.06 mmol) in 9 mL of toluene was purged with N₂ (3 cycles ofalternating N₂ and vacuum). The mixture was heated to 80° C. (oil-bathtemperature). After 24 h, the mixture was cooled to room temperature andEtOAc (30 mL) and of water (10 mL) was added. After stirring 15 min, theprecipitate was collected by filtration. A ¹H NMR spectrum and ESI massspectrum of the solid (150 mg) indicated the product (TLC analysis ofthe organic layer of the filtrate detected only starting materials). Thecrude product was slurried in 2 N HCl and the mixture was filtered. Thefiltrate was neutralized with 10% aqueous NaOH and concentrated. Thematerial was slurried with MeOH and the solids removed by filtration.The concentrated material was slurried in CH₃CN and TFA was added toafford a solution. N,N-diisopropylethylamine was added to the solutionand the solid was collected by filtration, washing with CH₃CN followedby Et₂O to affordN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-pyridyl)-2,4-pyrimidinediamine(55 mg, 14%): R_(f) 0.42 (silica gel, 4:1:0.1:0.1 dichloromethane/ethylacetate/methanol/concentrated ammonium hydroxide); mp 251-253° C.; ¹HNMR (300 MHz, DMSO-d₆) δ 9.38 (s, 1H), 9.26 (s, 1H), 8.74 (s, 1H),8.20-8.17 (m, 1H), 8.09-8.08 (m, 2H), 7.29-7.28 (m, 1H), 7.23-7.17 (m,2H), 6.83-6.80 (m, 1H), 4.24 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 155.2,149.8, 142.9, 141.6, 140.5, 140.0, 139.8, 139.7, 137.5, 132.1, 124.8,123.0, 116.4, 115.1, 110.9, 64.1, 64.0; IR (ATR) 3264, 3195 cm⁻¹; APCIMS m/z 340 [C₁₇H₁₄FN₅O₂+H]⁺. Anal. Calcd for C₁₇H₁₄FN₅O₂.0.5H₂O: C,58.70; H, 4.20; N, 20.13. Found: C, 58.71; H, 4.20; N, 19.51.

7.3.694 (R920664):N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(4-n-hexyloxyphenyl)-2,4-pyrimidindiamine

To a magnetically stirred solution of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (0.25g, 0.89 mmol) in ethylene glycol (3.0 mL) under nitrogen at roomtemperature was added N,N-diisopropylethylamine (0.12 g, 0.89 mmol)followed by 4-hexyloxyaniline (0.27 g, 1.4 mmol). The reaction mixturewas heated to 170° C. for 5.5 h, cooled to room temperature andpartitioned between water (20 mL) and chloroform (20 mL). The aqueouslayer was extracted with chloroform (20 mL) and the combined organiclayers were dried (Na₂SO₄), filtered and concentrated in vacuo. Thecrude brown solid was purified by chromatography (silica gel, 2:1hexanes/ethyl acetate) to affordN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-n-hexyloxyphenyl)-2,4-pyrimidindiamine(0.09 g, 23%) as a white solid: R_(f) 0.53 (silica gel, 4:1chloroform/ethyl acetate); mp 115-117° C.; ¹H NMR (500 MHz, CDCl₃) δ7.90 (d, J=3.2 Hz, 1H), 7.40 (d, J=8.9 Hz, 2H), 7.29 (d, J=2.5 Hz, 2H),6.98 (d, J=8.8 Hz, 1H), 6.88-6.82 (m, 3H), 6.61 (s, 1H), 4.29 (d, J=3.1Hz, 4H), 3.94 (t, J=6.6, 6.7 Hz, 2H), 1.77 (m, 2H), 1.47 (m, 2H), 1.35(m, 4H), 0.92 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 156.3, 155.1, 150.3,143.6, 142.7, 140.3, 140.07 139.4, 133.0, 131.7, 121.9, 117.3, 115.0,114.7, 110.8, 68.6, 64.6, 31.8, 29.5, 25.9, 22.8, 14.2; IR (ATR) 3357cm⁻¹; ESI MS m/z 439 [C₂₄H₂₇FN₄O₃+H]⁺; HPLC (Method B) 98.5% (AUC),t_(R)=7.9 min. Anal. Calcd for C₂₄H₂₇FN₄O₃: C, 65.74; H, 6.21; N, 12.78.Found: C, 65.34; H, 6.19; N, 12.96.

7.3.695 (R920666):N2-(4-n-Butyloxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine

To a magnetically stirred solution of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (0.25g, 0.89 mmol) in ethylene glycol (3.0 mL) under nitrogen at roomtemperature was added N,N-diisopropylethylamine (0.12 g, 0.89 mmol)followed by 4-butoxyaniline (0.18 g, 1.1 mmol). The reaction mixture washeated to 185° C. for 5 h, cooled to room temperature, and partitionedbetween water (20 mL) and ethyl acetate (20 mL). The aqueous layer wasextracted with ethyl acetate (20 mL) and the combined organic layerswere dried (Na₂SO₄), filtered and concentrated in vacuo. The crude brownsolid was purified by chromatography (silica gel, 2:1 hexanes/ethylacetate) to affordN2-(4-n-Butyloxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine(0.18 g, 49%) as a tan solid: R/0.66 (silica gel, 4:1 chloroform/ethylacetate); mp 133-135° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J=3.2 Hz,1H), 7.39 (d, J=8.9 Hz, 2H), 7.28 (d, J=2.5 Hz, 1H), 6.95 (dd, J=8.7,2.5 Hz, 1H) 6.90-6.81 (m, 4H), 6.60 (d, J=2.4 Hz, 1H), 4.27 (s, 4H),3.94 (t, J=6.5 Hz, 2H), 1.80-1.71 (m, 2H), 1.55-1.42 (m, 2H), 0.97 (t,J=7.3 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 156.3, 155.1, 150.4, 143.6,142.7, 140.3, 140.0, 139.4, 133.0, 131.7, 121.9, 117.3, 115.0, 114.7,110.8, 68.2, 64.7, 64.5, 31.6, 19.4, 14.0; IR (ATR) 3356 cm⁻¹; ESI MSm/z 411 [C₂₂H₂₃FN₄O₃+H]⁺; HPLC (Method A)>99% (AUC), t_(R)=17.3 min.Anal. Calcd for C₂₂H₂₃FN₄O₃: C, 64.38; H, 5.65; N, 13.65. Found: C,62.64; H, 5.59; N, 13.15.

7.3.696 (R920670):N4-(4-ethyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine

To a solution of2-chloro-N4-(4-ethyloxyphenyl)-5-fluoro-4-pyrimidineamine (0.25 g, 0.93mmol) in ethylene glycol (3 mL) under nitrogen at room temperature wasadded i-Pr₂EtN, 0.93 mmol) followed by 3,4-ethylenedioxyaniline (0.17 g,1.12 mmol). The reaction mixture was heated to 200° C. for 5 h and thencooled to room temperature. The mixture was partitioned between H₂O (20mL) and EtOAc (20 mL) and the aqueous layer was extracted with EtOAc (20mL). The combined organic layers were dried (Na₂SO₄), filtered, andconcentrated in vacuo.

The crude brown solid was purified by chromatography (2:1 CHCl₃/EtOAc)to affordN4-(4-ethyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(0.21 g, 60%) as a tan solid: R_(f) 0.42 (4:1 CHCl₃/EtOAc); mp163.8-167.2° C. (DSC); ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J=2.8 Hz, 1H),7.50-7.45 (m, 2H), 7.17 (d, J=2.5 Hz, 1H), 6.92-6.86 (m, 3H), 6.80-6.75(m, 2H), 6.64 (bs, 1H), 4.26-4.21 (m, 4H), 4.03 (q, J=7.0, 2H), 1.42 (t,J=6.9 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 156.1, 150.6, 143.6, 142.8,140.3, 140.0, 139.5, 139.3, 134.0, 130.8, 123.2, 117.2, 115.1, 113.6,109.4, 64.6, 64.0, 15.1; IR (ATR) 3403 cm⁻¹; ESI MS m/z 383[C₂₀H₁₉FN₄O₃+H]⁺; HPLC (Method A) 98.1% (AUC), t_(R)=12.0 min. Anal.Calcd for C₂OH₁₉FN₄O₃: C, 62.82; H, 5.01; N, 14.65. Found: C, 62.06; H,5.01; N, 14.35.

7.3.697 (R920671):N4-(4-n-Butyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine

In like manner to the preparation ofN4-(4-ethyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(4-n-butyloxyphenyl)-5-fluoro-4-pyrimidineamine with3,4-ethylenedioxyaniline gaveN4-(4-n-butyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine.The crude product was purified by chromatography (2:1 CHCl₃/EtOAc);(0.17 g, 52%) as a tan solid: R_(f) 0.51 (4:1 CHCl₃/EtOAc); mp149.6-151.4° C. (DSC); ¹H NMR (300 MHz, CDCl₃) δ 7.88 (d, J=3.4 Hz, 1H),7.47 (d, J=8.8 Hz, 2H), 7.18 (d, J=2.4 Hz, 1H), 6.91-6.86 (m, 3H),6.78-6.75 (m, 2H), 6.62 (bs, 1H), 4.26-4.22 (m, 4H), 3.96 (t, J=6.5,2H), 1.82-1.73 (m, 2H), 1.56-1.44 (m, 2H), 0.98 (t, J=7.4 Hz, 3H); ¹³CNMR (75 MHz, CDCl₃) δ 156.1, 150.8, 143.6, 142.8, 140.2, 139.9, 139.5,139.2, 133.9, 130.7, 123.1, 117.1, 115.0, 113.5, 109.4, 68.2, 64.6,31.6, 19.4, 14.0; IR (ATR) 3365 cm⁻¹; ESI MS m/z 411 [C₂₂H₂₃FN₄O₃+H]⁺;HPLC (Method A) 99.0% (AUC), t_(R)=13.2 min. Anal. Calcd forC₂₂H₂₃FN₄O₃: C, 64.38; H, 5.65; N, 13.65. Found: C, 63.63; H, 5.60; N,13.38.

7.3.698 (R920672):N4-(4-n-Hexyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine

In like manner to the preparation ofN4-(4-ethyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(4-n-hexyloxyphenyl)-5-fluoro-4-pyrimidineamine with3,4-ethylenedioxyaniline gaveN4-(4-n-hexyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine.The crude product was purified by chromatography (2:1 CHCl₃/EtOAc) (0.22g, 69%) as a tan solid: R_(f) 0.54 (4:1 CHCl₃/EtOAc); mp 124.0-125.2° C.(DSC); ¹H NMR (300 MHz, CDCl₃) δ 7.88 (d, J=3.2 Hz, 1H), 7.47 (d, J=8.9Hz, 2H), 7.18 (d, J=2.4 Hz, 1H), 6.91-6.86 (m, 3H), 6.78-6.74 (m, 2H),6.62 (d, J=1.8 Hz, 1H), 4.26-4.22 (m, 4H), 3.96 (t, J=6.5, 2H),1.83-1.74 (m, 2H), 1.51-1.42 (m, 2H), 1.36-1.32 (m, 4H), 0.93-0.89 (t,J=6.7 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 156.1, 150.5, 143.5, 143.0,142.8, 140.2, 139.9, 139.5, 139.2, 133.9, 130.7, 123.1, 117.1, 115.0,113.5, 109.3, 68.5, 64.7, 64.5, 31.8, 29.5, 25.9, 22.8, 14.2; IR (ATR)3378 cm⁻¹; ESI MS m/z 439 [C₂₄H₂₇FN₄O₃+H]⁺; HPLC (Method A)>99% (AUC),t_(R)=14.6 min. Anal. Calcd for C₂₄H₂₇FN₄O₃: C, 65.74; H, 6.21; N,12.78. Found: C, 65.52; H, 6.23; N, 12.66.

7.3.699 (R920818):5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

To a mixture of 4-amino-[(1,2,3,4-tetrazol-5-yl)methyleneoxy]benzene(1.2 g, 6.2 mmol), 1-propanol (40 mL) and trifluoroacetic acid (1 mL)was added 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyridineamine (1.5 g,6.2 mmol). The mixture was heated at 110° C. for 17 h and then cooled toroom temperature. The purple solid that formed was collected byfiltration, washing with 1-propanol (30 mL) to afford5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(1.6 g, 65%) as an off-white solid: R_(f) 0.55 (6:3:1CHCl₃/CH₃OH/NH₄OH); mp (DSC) 191.2-193.7° C., 257.2-260.0° C.,344.7-345.2° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 9.39 (s, 1H), 9.21 (s, 1H),9.10 (s, 1H), 8.04 (d, J=3.8 Hz, 1H), 7.59 (d, J=9.1 Hz, 2H), 7.38 (s,1H), 7.23 (t, J=8.1 Hz, 1H), 7.17 (d, J=1.8 Hz, 1H), 7.05 (t, J=8.1 Hz,1H), 6.93 (d, J=9.1 Hz, 2H), 6.50 (dd, J=1.8, 8.1 Hz, 1H), 5.40 (s, 2H);¹³C NMR (75 MHz, DMSO-d₆) δ 157.3, 155.3, 153.5, 151.9, 149.8, 149.7,141.0 (d, J_(C-F)=150.0 Hz), 139.7, 138.7, 135.0, 128.9, 120.2, 114.8,110.3, 108.7, 59.6; IR (ATR) 3338, 2923, 2581, 1724, 1661, 1580, 1557cm⁻¹; ESI MS m/z 395 [C₁₈H₁₅FN₈O₂+H]⁺; HPLC (Method A) 96.5% (AUC),t_(R)=6.9 min.

7.3.700 (R920819):N4-(3-Hydroxyphenyl)-N2-[4-(1H,1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

To a mixture of 4-amino-[(1H,1,2,3,4-tetrazolyl)methyleneoxy]benzene(0.1 g, 0.5 mmol), 1-propanol (2 mL) and trifluoroacetic acid (0.2 mL)was added 2-chloro-N4-(3-hydroxyphenyl)-4-pyrimidineamine (0.1 g, 0.5mmol). The mixture was heated at 110° C. for 17 h and then cooled toroom temperature. The purple solid that formed was collected byfiltration, washing with 1-propanol (5 mL) to affordN4-(3-hydroxyphenyl)-N2-[4-(1H,1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine (59.4mg, 30%) as an off-white solid: R_(f) 0.51 (6:3:1 CHCl₃/CH₃OH/NH₄OH); mp292-295° C. dec; ¹H NMR (300 MHz, DMSO-d₆) δ 9.34 (s, 2H), 9.13 (s, 1H),7.95 (d, J=5.8 Hz, 1H), 7.64 (d, J=8.9 Hz, 2H), 7.39 (s, 1H), 7.19 (t,J=8.1 Hz, 1H), 7.05 (t, J=8.1 Hz, 1H), 6.96 (d, J=8.9 Hz, 2H), 6.43 (dd,J=1.4, 8.1 Hz, 1H), 6.20 (d, J=5.8 Hz, 1H), 5.40 (s, 2H); ¹³C NMR (75MHz, DMSO-d₆) δ 160.4, 158.5, 157.5, 154.0, 153.7, 152.2, 140.6, 134.4,129.1, 120.9, 114.7, 111.0, 109.5, 107.2, 98.4, 59.6; IR (ATR) 3321,2920, 2581, 1649, 1605, 1487 cm⁻¹; ESI MS m/z 377 [C₁₈H₁₆N₈O₂+H]⁺; HPLC(Method A) 97.6% (AUC), t_(R)=7.6 min.

7.3.701 (R920820): N4-(3-Hydroxyphenyl)-5-methyl-N2-[4-(1H,1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

To a mixture of 4-amino-[(1H,1,2,3,4-tetrazolyl)methyleneoxy]benzene(0.2 g, 0.9 mmol), 1-propanol (4 mL) and trifluoroacetic acid (0.2 mL)was added 2-chloro-N4-(3-hydroxyphenyl)-5-methyl-4-pyrimidineamine (0.2g, 0.9 mmol). The mixture was heated at 110° C. for 17 h and then cooledto room temperature. The purple solid that formed was collected byfiltration, washing with 1-propanol (10 mL) to affordN4-(3-hydroxyphenyl)-5-methyl-N2-[4-(1H,1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine (0.3 g,89%) as an off-white solid: R_(f)0.44 (6:3:1 CHCl₃/CH₃OH/NH₄OH); mp(DSC) 255.3-262.4° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 10.32 (s, 1H), 9.65(s, 2H), 7.85 (s, 1H), 7.38 (d, J=10.5 Hz, 2H), 7.17 (s, 1H), 7.12 (t,J=7.9 Hz, 1H), 7.06 (s, 1H), 6.90 (d, J=10.5 Hz, 2H), 6.68 (d, J=7.9 Hz,1H), 5.45 (s, 2H), 2.14 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 161.6,157.9, 154.5, 153.7, 151.2, 140.4, 138.2, 130.1, 129.4, 123.3, 115.9,115.4, 113.5, 112.4, 107.5, 59.8, 13.7; IR (ATR) 3214, 3051, 2157, 1632,1596, 1547 cm⁻¹; ESI MS m/z 391 [C₁₉H8N₈O₂+H]⁺; HPLC (Method A)>99%(AUC), t_(R)=7.9 min.

7.3.702N4-(3-Benzyloxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine[NEEDR NO.]

A mixture of N4-(3-benzyloxyphenyl)-2-chloro-4-pyrimidineamine (0.25 g,0.82 mmol),4-amino-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene (0.17 g,0.82 mmol) and trifluoroacetic acid (0.2 mL) in 1-propanol (10 mL) washeated to 110° C. for 24 h. The reaction was concentrated to remove mostof the 1-propanol, the crude product was preadsorbed onto silica gelusing 95:5 methylene chloride/methanol and purified by flashchromatography (95:5 methylene chloride/methanol) to giveN4-(3-benzyloxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamineas a tan solid (0.20 g, 52%): ¹H NMR (300 MHz, DMSO-d₆) δ 8.00 (br s,1H), 7.86 (d, J=6.1 Hz, 1H), 7.53-7.20 (m, 13H), 7.14 (d, J=9.0 Hz, 2H),6.93 (d, J=6.1 Hz, 1H), 6.13 (d, J=6.1 Hz, 1H), 5.27 (s, 2H), 4.04 (s,3H); ESI MS m/z 481 [C₂₆H₂₄N₈O₂+H]⁺

7.3.703 (R920917):N4-(3-hydroxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine

A mixture ofN4-(3-benzyloxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine(0.20 g, 0.42 mmol) and 5% Pd/C (0.10 g) in 14:1 ethanol/concentratedhydrochloric acid (40 mL) was at room temperature was shaken in ahydrogen atmosphere at 50 psi. After 3 h no further hydrogen uptake wasobserved. The reaction mixture was filtered through diatomaceous earth,the solids washed with 95:5 methylene chloride/methanol and the filtrateconcentrated to affordN4-(3-hydroxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine(0.16 g, 95%) as a tan solid: R/0.23 (95:5 methylene chloride/methanol);mp (DSC) 207.1-212.8, 287.4-295.7° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 10.87(br s, 1H), 10.81 (br s, 1H), 9.62 (br s, 1H), 8.08-8.06 (m, 1H), 7.72(d, J=9.0 Hz, 2H), 7.24 (br s, 1H), 7.20-7.00 (m, 3H), 6.61 (m, 2H),6.46, (d, J=6.0 Hz, 1H), 5.38 (s, 2H), 4.40 (s, 3H); ¹³C NMR (75 MHz,DMSO-d₆) δ 161.3, 160.1, 157.0, 154.3, 151.6, 141.7, 137.6, 129.1,128.6, 123.4, 114.4, 111.9, 111.5, 108.3, 98.6, 59.6, 38.0; IR (ATR)2975, 1639, 1602, 1521 cm⁻¹; ESI MS m/z 391 [C₁₉H8N₈O₂+H]⁺; HPLC (MethodA) 94.9% (AUC), t_(R)=8.19 min.

7.3.704N4-(3-Benzyloxyphenyl)-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine[NEEDR NO.]

A mixture of N4-(3-benzyloxyphenyl)-2-chloro-4-pyrimidineamine (0.52 g,1.69 mmol), 4-amino-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]benzene(0.34 g, 1.69 mmol) and trifluoroacetic acid (0.4 mL) in 1-propanol (10mL) was heated to 110° C. for 24 h. The reaction was concentrated toremove most of the 1-propanol. The crude product was preadsorbed ontosilica gel using 95:5 methylene chloride/methanol and purified by flashchromatography (95:5 methylene chloride/methanol) affording therequisite productN4-(3-benzyloxyphenyl)-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl)-2,4-pyrimidineamineas a tan solid (0.41 g, 51%): ¹H NMR (300 MHz, DMSO-d₆) δ 7.85 (d, J=6.1Hz, 1H), 7.49-7.04 (m, 14H), 6.93 (d, J=9.0 Hz, 2H), 6.60-6.72 (m, 1H),6.11 (d, J=6.1 Hz, 1H), 5.14 (s, 2H), 4.34 (s, 3H); ESI MS m/z 481[C₂₆H₂₄N₈O₂+H]+

7.3.705 (R920910):N4-(3-Hydroxyphenyl)-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine

A mixture ofN4-(3-benzyloxyphenyl)-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine(0.40 g, 0.42 mmol) and 5% Pd/C (0.10 g) in 14:1 ethanol/concentratedhydrochloric acid (40 mL) at room temperature was shaken in anatmosphere of hydrogen at 50 psi. After 3 h no further hydrogen uptakewas observed. The reaction mixture was filtered through diatomaceousearth, the solids washed with 95:5 methylene chloride/methanol and thefiltrate concentrated to affordN4-(3-hydroxyphenyl)-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine(0.29 mg, 89%) as a beige solid: R/0.43 (95:5 methylenechloride/methanol); mp 140-152° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 10.24(br s, 1H), 9.98 (br s, 1H), 9.52 (br s, 1H), 7.94 (d, J=6.6 Hz, 2H),7.54 (d, J=8.8 Hz, 2H), 7.43 (s, 1H), 7.26 (s, 1H), 7.18-7.01 (m, 3H),6.53, (d, J=7.5 Hz, 1H), 6.37, (d, J=6.6 Hz, 1H), 5.52 (s, 2H), 4.13 (s,3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 160.2, 157.2, 154.5, 153.0, 151.2,146.8, 139.9, 131.8, 128.7, 122.3, 114.7, 111.4, 110.5, 107.5, 99.5,59.5, 33.3; IR (ATR) 3042, 1578, 1504, 1459 cm⁻¹; ESI MS m/z 391[C₁₉H₁₈N₈O₂+H]⁺; HPLC (Method A) 95.8% (AUC), t_(R)=8.82 min.

7.3.706 (R920861):5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine

A mixture of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine(0.22 g, 0.93 mmol,4-amino-[(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene (0.19 g,0.93 mmol) and trifluoroacetic acid (0.2 mL) in 1-propanol (8 mL) washeated to 110° C. for 24 h. The reaction was concentrated to remove mostof the 1-propanol. The crude product was preadsorbed onto silica gelusing 95:5 methylene chloride/methanol and purified by flashchromatography (95:5 methylene chloride/methanol) affording therequisite product5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamineas a purple solid (0.18 g, 49%): R_(f) 0.47 (95:5 methylenechloride/methanol); mp 219-224° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 9.36 (s,1H), 9.18 (s, 1H), 9.06 (s, 1H), 8.05 (d, J=6.0 Hz, 1H), 7.60 (d, J=9.0Hz, 2H), 7.27 (d, J=9.0 Hz, 1H), 7.09 (t, J=8.0 Hz, 2H), 6.94 (d, J=9.0Hz, 2H), 6.49 (dd, J=8.0, 2.1 Hz, 1H), 5.45 (s, 2H), 4.11 (s, 3H); ¹³CNMR (75 MHz, DMSO-d₆) δ 157.4, 155.5, 151.7, 151.6, 149.6, 149.5, 142.0,142.0, 139.3 (d, J_(C-F)=127.5 Hz), 135.3, 128.9, 120.1, 114.9, 112.3,110.3, 108.5, 58.5, 33.9; IR (ATR) 3278, 1586, 1542, 1508 cm⁻¹; ESI MSm/z 409 [C₁₉H₁₇FN₈O₂+H]⁺; HPLC (Method A) 98.2% (AUC), t_(R)=7.69 min.Anal. Calcd for C₁₉H₁₇FN₈O₂.0.5H₂O: C, 54.74; H, 4.23; N, 26.88. Found:C, 54.55; H, 4.02; N, 26.62.

7.3.707 (R920860):5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine

A mixture of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine(0.31 g, 1.28 mmol),4-amino-[(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene (0.26 g,1.28 mmol) and trifluoroacetic acid (0.2 mL) in 1-propanol (8 mL) washeated at 110° C. for 24 h. The reaction was concentrated to remove mostof the 1-propanol. The crude product was preadsorbed onto silica gelusing 95:5 methylene chloride/methanol and purified by flashchromatography (95:5 methylene chloride/methanol) to give5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamineas a purple solid (0.20 g, 37%): R/0.63 (95:5 methylenechloride/methanol); mp 220-224° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 9.36 (s,1H), 9.17 (s, 1H), 9.02 (s, 1H), 8.05 (d, J=2.8 Hz, 1H), 7.57 (d, J=9.1Hz, 2H), 7.27 (d, J=8.0 Hz, 1H), 7.10 (dt, J=2.8, 8.0 Hz, 2H), 6.91 (d,J=9.1 Hz, 2H), 6.49 (dd, J=8.0, 2.8 Hz, 1H), 5.29 (s, 2H), 4.39 (s, 3H);¹³C NMR (75 MHz, DMSO-d₆) δ 162.2, 157.4, 155.5, 152.1, 149.6, 149.5,140.9 (d, J_(C-F)=142.0 Hz), 140.5, 140.2, 138.7, 134.8, 128.9, 120.2,114.5, 112.2, 110.2, 108.5, 60.5, 38.5; IR (ATR) 3274, 1587, 1507 cm⁻¹;ESI MS m/z 409 [C₁₉H₁₇FN₈O₂+H]⁺; HPLC (Method A) 97.2% (AUC), t_(R)=8.04min. Anal. Calcd for C₁₉H₁₇FN₈O₂.: C, 55.88; H, 4.20; N, 27.44. Found:C, 55.56; H, 4.10; N, 27.17.

7.3.708 (R920894):N4-(3-Hydroxyphenyl)-5-methyl-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine

A mixture of 2-chloro-N4-(3-hydroxyphenyl)-5-methyl-4-pyrimidineamine(0.20 g, 0.85 mmol,4-amino-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene (0.17 g,0.85 mmol) and trifluoroacetic acid (0.2 mL) in 1-propanol (8 mL) washeated at 110° C. for 24 h. The reaction was concentrated to remove mostof the 1-propanol. The crude product was preadsorbed onto silica gelusing 95:5 methylene chloride/methanol and purified by flashchromatography (95:5 methylene chloride/methanol) to giveN4-(3-hydroxyphenyl)-5-methyl-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamineas a purple solid (0.18 g, 52%): R_(f) 0.61 (95:5 methylenechloride/methanol); mp 209-211° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (s,1H), 8.82 (s, 1H), 8.13 (s, 1H), 7.83 (s, 1H), 7.60 (d, J=9.0 Hz, 2H),7.18-7.05 (m, 3H), 6.89 (d, J=9.0 Hz, 2H), 6.48 (t, J=7.1 Hz, 1H), 5.27(s, 2H), 4.39 (s, 3H), 2.08 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 161.7,158.6, 157.5, 156.7, 154.7, 151.2, 140.2, 134.6, 134.6, 128.1, 119.3,114.0, 112.6, 109.4, 108.9, 104.7, 59.8, 38.0, 12.9; IR (ATR) 3003,1602, 1581, 1531, 1507 cm⁻¹; ESI MS m/z 405 [C₂₀H₂₀N₈O₂+H]⁺; HPLC(Method A) 96.8% (AUC), t_(R)=8.23 min.

7.3.709 (R920893):N4-(3-Hydroxyphenyl)-5-methyl-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine

A mixture of 2-chloro-N4-(3-hydroxyphenyl)-5-methyl-4-pyrimidineamine(0.20 g, 0.85 mmol),4-amino-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene (0.17 g,0.85 mmol) and trifluoroacetic acid (0.2 mL) in 1-propanol (8 mL) washeated at 110° C. for 24 h. The reaction was concentrated to remove mostof the 1-propanol. The crude product was preadsorbed onto silica gelusing 95:5 methylene chloride/methanol and purified by flashchromatography (95:5 methylene chloride/methanol) to giveN4-(3-Hydroxyphenyl)-5-methyl-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamineas a purple solid (0.14 g, 42%): R/0.44 (95:5 methylenechloride/methanol); mp 219-221° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (s,1H), 8.85 (s, 1H), 8.13 (s, 1H), 7.85 (s, 1H), 7.64 (d, J=9.0 Hz, 2H),7.20-7.07 (m, 3H), 6.91 (d, J=9.0 Hz, 2H), 6.50 (dd, J=8.0, 1.2 Hz, 1H),5.45 (s, 2H), 4.12 (s, 3H), 2.09 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ158.0, 157.0, 156.1, 154.3, 150.6, 150.0, 139.6, 134.6, 127.5, 118.6,113.7, 112.0, 108.8, 108.2, 104.2, 57.4, 32.7, 12.3; IR (ATR) 3428,1595, 1567, 1509 cm⁻¹; ESI MS m/z 405 [C₂₀H₂₀N₈O₂+H]⁺; HPLC (Method A)98.5% (AUC), t_(R)=7.89 min. Anal. Calcd for C₂₀H₂₀N₈O₂. H₂O: C, 57.00;H, 5.02; N, 26.59. Found: C, 56.86; H, 4.92; N, 26.50.

7.3.710N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-(1,2,3,4-tetrazol-5-yl)-2,4-pyrimidinediamine(R925810)

In a manner similar to experiment #,N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-cyano-2,4-pyrimidinediamineand sodium azide were reacted to yieldN2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-(1,2,3,4-tetrazol-5-yl)-2,4-pyrimidinediamine.LCMS: ret. time: 25.8 min.; purity: 95%; MS: 535 (MH⁺).

7.3.711 N2-[4-(N-Cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-5-ethoxycarbonyl-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R925838)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-ethoxycarbonyl-N4-(3-hydroxyphenyl)-N2-(methoxycarbonylmethyleneoxyphenyl)-2,4-pyridinediaminewith cyclopropylmethylamine gaveN2-[4-(N-cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-5-ethoxycarbonyl-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: MS (m/e): 478 (MH⁺).

7.3.7125-Ethoxycarbonyl-N4-(3-hydroxyphenyl)-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R925839)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-ethoxycarbonyl-N4-(3-hydroxyphenyl)-N2-(methoxycarbonylmethyleneoxyphenyl)-2,4-pyridinediaminewith methylamine hydrochloride gave5-ethoxycarbonyl-N4-(3-hydroxyphenyl)-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.LCMS: MS (m/e): 438 (MH⁺).

7.3.713 N2-[4-(N-2,3-Dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-ethoxycarbonyl-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R925840)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-ethoxycarbonyl-N4-(3-hydroxyphenyl)-N2-(methoxycarbonylmethyleneoxyphenyl)-2,4-pyridinediaminewith 3-amino-1,2-propanediol gaveN2-[4-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-ethoxycarbonyl-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: MS (m/e): 498 (MH⁺).

7.3.714 N2,N4-Bis[4-[N-(3-methoxybenzylamino)carbonylmethyleneoxy]phenyl]-5-bromo-2,4-pyrimidinediamine (R925841)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN2,N4-bis[4-ethoxycarbonylmethyleneoxyphenyl)-5-bromo-2,4-pyrimidinediaminewith 3-methoxybenzylamine gave N2,N4-bis[4-[N-(3-methoxybenzylamino)carbonylmethyleneoxy]phenyl]-5-bromo-2,4-pyrimidinediamine. LCMS: ret.time: 25.94 min.; purity: 95%; MS (m/e): 727 (MH⁺).

7.3.715 5-Bromo-N4-[4-[(N-cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R925842)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-bromo-N4-(4-ethoxycarbonylmethyleneoxyphenyl)-N2-(3-hydroxyphenyl)-2,4-pyrimidinediaminewith cyclopropylmethylamine gave5-bromo-N4-[4-(N-cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 20.63 min.; purity: 100%; MS (m/e): 485 (MH⁺).

7.3.7165-Bromo-N2-(3-hydroxyphenyl)-N4-[4-(N-3-methoxybenzylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R925843)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-bromo-N4-(4-ethoxycarbonylmethyleneoxyphenyl)-N2-(3-hydroxyphenyl)-2,4-pyrimidinediaminewith 3-methoxybenzylamine gave5-bromo-N2-(3-hydroxyphenyl)-N2-(3-hydroxyphenyl)-N4-[4-(N-3-methoxybenzylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 22.34 min.; purity: 90%; MS (m/e): 551 (MH⁺).

7.3.717N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-carboxybenzofuran-5-yl)-2,4-pyrimidinediamine(R926698)

In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-(2,3-dihydro-2-carboxybenzofuran-5-yl)-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamineand LiOH were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-carboxybenzofuran-5-yl)-2,4-pyrimidinediamine.

7.3.718N2,N4-Bis(4-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine(R926016)

In a manner similar to the preparation ofN2-N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidineamine, the reaction of2,4-dichloro-5-fluoropyrimidine with 4-trifluoromethylaniline gaveN2,N4-bis(4-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ 8.06 (bs, 1H), 7.75 (d, 2H, J=9 Hz), 7.67 (d, 2H, J=9Hz), 7.63 (d, 2H, J=9 Hz), 7.54 (d, 2H, J=9 Hz), 7.19 (bs, 1H), 6.96 (s,1H); ¹⁹F NMR (CDCl₃): δ −17598 (s, 3F), −17676 (s, 3F), −46549 (s, 1F);HPLC: 85% pure.

7.3.719N2-(3,4-Ethylenedioxyphenyl)-N4-(3,4-methylenedioxyphenylhydrazinyl)-5-fluoro-2-pyrimidineamine(R926406)

In a manner similar to the preparation ofN2-(3-hydroxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidineamine,the reaction of 2-chloro-5-fluoroN4-(3,4-methylenedioxyphenylhydrazinyl)-4-pyrimidineamine with3,4-ethylenedioxyaniline gaveN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-(3,4-methylenedioxyphenylhydrazinyl)-2-pyrimidineamine.¹H NMR (CD₃OD): δ 7.82 (d, 1H, J=3.6 Hz), 7.52 (dd, 1H, J=1.8 and 7.5Hz), 7.40 (d, 1H, J=1.2 Hz), 7.14 (d, 1H, J=2.4 Hz), 6.92 (d, 1H, J=8.4Hz), 6.85 (dd, 1H, J=2.1 and 8.7 Hz), 6.45 (d, 1H, J=9 Hz), 6.06 (s,2H), 4.10 (s, 4H); LCMS: ret. time: 12.14 min.; purity: 88%; MS (m/e):426 (MH⁺).

7.3.720N2,N4-Bis(4-ethoxycarbonylmethylenedioxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine(R926566)

To a solution of 2,4-dichloro-5-nitropyrimidine (0.264 g, 1 mmol) inEtOAc (10 mL) at 0° C. was added diisopropylethyl amine (0.200 mL)followed by ethyl 4-aminophenoxy acetate (0.585 g, 3 mmol) and thenshaken at room temperature for 2 h. The reaction was quenched with waterand extracted with EtOAc. The EtOAc extract was washed with 2N HCl andwater. The solvent was evaporated and the residue was purified bycrystallization using EtOAc/hexanes to affordN2,N4-bis(4-ethoxycarbonylmethylenedioxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine(R926566). ¹H NMR (CDCl₃): 10.32 (s, 1H), 7.42 (s, 1H), 7.40 (d, 2H,J=8.7 Hz), 7.32 (d, 2H, J=8.7 Hz), 6.93 (d, 2H, J=8.7 Hz), 6.82 (d, 2H,J=8.7 Hz), 4.67 (s, 2H), 4.62 (s, 2H), 4.47 (q, 2H, J=7.5 Hz), 4.30 (m,4H), 1.42 (t, 3H, J=6.9 Hz), 1.31 (m, 6H); LCMS: ret. time: 32.10 min.;purity: 100%; MS (m/e): 584 (MH⁺).

7.3.721N2,N4-Bis[2-(methylthio)-1,3-benzothiaz-6-yl]-5-fluoro-2,4-pyrimidinediamine(R950202)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-fluoropyrimidine and2-(methylthio)-1,3-benzothiazol-6-amine were reacted to prepareN2,N4-bis[2-(methylthio)-1,3-benzothiaz-6-yl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 24.98 min.; purity: 84.6%; MS (m/e): 486.80 (MH⁺).

7.3.722N4-[3-(2-Hydroxyethyleamino)phenyl]-N2-[3-(N—(N-methyl)-piperazino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine(R950240)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamineand N-methylpiperazine were reacted to giveN4-[3-(2-hydroxyethylenoxy)phenyl]-N2-[3-(N—(N-methyl)-piperazino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 13.36 min.; purity: 97.6%; MS (m/e): 495.42 (MH⁺).

7.3.723N4-[3-(2-Hydroxyethyleamino)phenyl]-N2-[3-(N-piperazino)-carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine(R950241)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethyleneamino)phenyl]-2,4-pyrimidinediamineand piperazine were reacted to giveN4-[3-(2-hydroxyethyleneamino)phenyl]-N2-[3-(N-piperazino)-carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 13.21 min.; purity: 100%; MS (m/e): 481.40 (MH⁺).

7.3.724(+)-N4-(3-Aminophenyl)-5-fluoro-N2-(3-(3-carboxy-3-D,L-N-phtaloylamino)propylenecarbonylaminophenyl)-2,4-pyrimidinediamine(R950251)

N2,N4-Bis(4-aminophenyl)-5-fluoro-2,4-pyrimidinediamine andN-phtaloyl-DL-glutamic anhydride were reacted in DMF to giveN4-(3-aminophenyl)-5-fluoro-N2-(3-(3-carboxy-3-D,L-N-phtaloylamino)propylenecarbonylaminophenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 19.41 min.; purity: 95.7%; MS (m/e): 569.98 (MH⁺).

7.3.725(+)-N4-(3-Aminophenyl)-5-fluoro-N2-[3-(3-carboxy-3-amino)propylenecarbonylaminophenyl]-2,4-pyrimidinediamine(R950255)

(+)-N4-(3-Aminophenyl)-5-fluoro-N2-[3-(3-carboxy-3-D,L-N-phtaloylamino)propylenecarbonylaminophenyl]-2,4-pyrimidinediaminewas reacted with hydrazine to giveN4-(3-aminophenyl)-5-fluoro-N2-[3-(3-carboxy-3-amino)propylenecarbonylaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 11.98 min.; purity: 90.1%; MS (m/e): 440.3 (MH⁺).

7.3.726 5-Methoxycarbonyl-N2,N4-bis[4-(N-pyrrolidino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (R926559)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-ethoxycarbonyl-N2,N4-bis(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewith pyrrolidine gave 5-methoxycarbonyl-N2,N4-bis[4-(N-pyrrolidino)methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine. The ethylester at 5-position was exchanged to methyl ester in methanol as asolvent. MS (m/e): 575 (MH⁺).

7.3.727N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyridinediamine(R925565)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-fluoropyrimidine with ethyl 4-aminophenoxyacetate gaveN2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyridinediamine.MS (m/e): 485 (MH⁺).

7.3.728N2-(3-Ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-N4-(3,4-tetrafluoroethylenedioxyphenyl)-2,4-pyrimidinediamine(R926799)

In a manner similar to the preparation ofN2-(3-hydroxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidineamine,the reaction of ethyl 3-aminophenoxyacetate with2-chloro-5-ethoxycarbonyl-N4-(3,4-tetrafluoroethylenedioxyphenyl)-4-pyrimidineaminegaveN2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-N4-(3,4-tetrafluoroethylenedioxyphenyl)-2,4-pyrimidinediamine.MS (m/e): 567 (MH⁺).

7.3.729N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[N-2-(D)-(+)-biotinylethylamino]carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926811)

To a solution of D-(+)-biotin andN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein DMF at −20° C. was added diisopropylethylamine and the mixture wasshaken for 10 minutes. To this mixture was addedbenzotriazole-1-yl-oxy-tris(dimethylamino)-phosphoniumhexafluorophosphate(BOP) and shaken at room temperature for 24 h. The reaction was quenchedwith water and extracted with ethyl acetate. The ethyl acetate extractwas washed with aqueous solution of NaHCO₃ and finally with water. Theresidue obtained after the removal of solvent was purified bypreparative TLC to obtain the desiredN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[N-2-(D)-(+)-biotinylethylamino]carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 19.29 min.; purity: 99%; MS (m/e): 682 (M⁺).

7.3.730 5-Fluoro-N4-(3-hydroxyphenyl)-N2[2-(N-methyl-N-2-hydroxyethyl)carbonylbenzofuran-5-yl)-2,4-pyrimidinediamine(R926725)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-fluoro-N4-(3-hydroxyphenyl)-N2[2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediaminewith 2-(N-methyl)ethanolamine gave5-fluoro-N4-(3-hydroxyphenyl)-N2[2-(N-methyl-N-2-hydroxyethyl)carbonylbenzofuran-5-yl)-2,4-pyrimidinediamine.LCMS: ret. time: 14.87 min.; purity: 98%; MS: 438 (MH⁺).

7.3.731 N2,N4-Bis(3-ethoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R926228)

In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-fluoropyrimidine and 3-ethoxycarbonylaniline gaveN2,N4-bis(3-ethoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 26.55 min.; purity: 100%; MS (m/e): 425 (MH⁺).

7.3.732N2-(3-chloro-4-methylbenzyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R908696)

In a manner similar to the preparation ofN2-(3-hydroxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidineamine,the reaction of2-chloro-N4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with3-chloro-4-methylbenzylamine gaveN2-(3-chloro-4-methylbenzyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 25.38 min.; purity: 99%; MS (m/e): 401 (MH⁺).

7.3.733(+)-N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-phenylethyl)-2,4-pyrimidinediamine(R908697)

In a manner similar to the preparation ofN2-(3-hydroxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidineamine,the reaction of2-chloro-N4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with(+)-2-aminoethylbenzene gave(+)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-phenylethyl)-2,4-pyrimidinediamine.LCMS: ret. time: 23.48 min.; purity: 99%; MS (m/e): 367 (MH⁺).

7.3.734N2-(3-Ethoxycarbonylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R925745)

In like manner to preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3-ethoxycarbonylaniline gaveN2-(3-ethoxycarbonylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.04 (bs, 1H), 7.94 (bs, 1H), 7.90 (bd, 1H), 7.68 (bd,1H, J=7.5 Hz), 7.35 (t, 1H, J=8.1 Hz), 7.28 (d, 1H, J=2.4 Hz), 7.07 (s,1H), 6.93 (dd, 1H, J=3 and 8.7 Hz), 6.83 (d, 1H, J=9 Hz), 6.64 (bs, 1H),4.36 (q, 2H, J=7.2 Hz), 4.26 9s, 4H), 1.35 (t, 3H, J=7.5 Hz); ¹⁹F NMR(CDCl₃): −47247; LCMS: ret. time: 15.88.; purity: 100%; MS (m/e): 411(MH⁺).

7.3.735 N4-(3,4-Difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R920394)

A solution of N-methyl 3-aminophenoxyacetamide (1 equivalent) and2-chloro-N4-(3,4-difluorophenyl)-5-fluoro-4-pyrimidineamine (1.2equivalents) in MeOH was shaken in a sealed tube at 100° C. for 24 hoursfor 24 h. Upon cooling to the room temperature, it was diluted withethyl acetate. The resulting solid was filtered and washed with amixture of ethyl acetate: n-hexanes (1:1; v/v) to obtainN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.05 (bs, 1H), 9.83 (bs, 1H), 8.23 (d, 1H, J=2.7Hz), 7.98 (m, 2H), 7.52 (m, 1H), 7.39 9m, 1H), 7.20 (m, 3H), 6.60 (m,1H), 4.37 (s, 2H0, 2.63 (d, 3H, J=3.3 Hz); LCMS: purity: 94%; MS (m/e):404 (MH⁺).

7.3.736 N4-(4-Chlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R920396)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(4-chlorophenyl)-5-fluoro-4-pyrimidineamine gaveN4-(4-chlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.21 (bs, 1H), 10.00 (bs, 1H), 8.26 (d, 1H, J=4.8Hz), 8.00 (bd, 1H, J=4.2 Hz), 7.77 (dd, 2H, J=2.1 and 7.6 Hz), 7.37 (dd,2H, J=2.1 and 7.6 Hz), 7.17 9m, 3H), 8.63 (dd, 1H, J=1.8 and 8.1 Hz),4.37 (s, 2H), 2.64 (d, 3H, 4.5 Hz); LCMS: purity: 92%; MS (m/e): 402(MH⁺).

7.3.736.1 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R920397)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine gaveN4-(3,4-dichlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.02 (bs, 1H), 9.76 (bs, 1H), 8.24 (d, 1H, J=4.2Hz), 8.08 (m, 1H), 7.97 (bd, 1H, J=4.8 Hz), 7.77 (m, 1H), 7.55 (d, 1H,J=8.7 Hz), 7.18 (m, 3H), 6.58 (m, 1H), 4.36 (s, 1H), 2.63 (d, 1H, J=2.7Hz); LCMS: purity: 91%; MS: 434 (MH⁺).

7.3.737 5-Fluoro-N4-(5-methylpyridin-2-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R920398)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(5-methylpyridin-2-yl)-4-pyrimidineamine gave5-fluoro-N4-(5-methylpyridin-2-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 11.35 (bs, 1H), 10.70 (bs, 1H), 8.58 (s, 1H), 8.42(d, 1H, J=3.0 Hz), 8.12 (bd, 1H, J=9.3 Hz), 8.03 (bd, 1H, J=4.2 Hz),7.82 (d, 1H, J=8.7 Hz), 7.56 (s, 1H), 7.30 (bdd, 1H, J=8.1 Hz), 7.19 (t,1H, J=8.1 Hz), 6.55 (dd, 1H, J=1.8 and 8.1 Hz), 4.41 (s, 2H), 2.63 (d,3H, J=3.6 Hz), 2.36 (s, 3H); LCMS: purity: 99%; MS (m/e): 382 (M⁺).

7.3.738 5-Fluoro-N4-(6-methylpyridin-2-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R920399)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(6-methylpyridin-2-yl)-4-pyrimidineamine gave5-fluoro-N4-(6-methylpyridin-2-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.00 (bs, 1H), 9.60 (bs, 1H), 8.25 (s, 1H), 7.95(m, 3H), 7.30 (s, 1H), 7.10 (m, 3H), 6.55 (d, 1H, J=7.2 Hz), 4.40 (s,2H), 2.62 (d, 3H, J=3.6 Hz), 2.45 (s, 3H); LCMS: purity: 92%; MS (m/e):383 (MH⁺).

7.3.739 N4-(5-Chloropyridin-2-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (R920405)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(5-chloropyridin-2-yl)-5-fluoro-4-pyrimidineamine gaveN4-(5-chloropyridin-2-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.04 (bs, 1H), 9.53 (bs, 1H), 8.40 (d, 1H, J=2.4Hz), 8.22 (m, 2H), 7.88 (bd, 1H, J=4.5 Hz), 7.86 (dd, 1H, J=2.4 and 8.7Hz), 7.40 (d, 1H, J=1.8 Hz), 7.19 (m, 2H), 6.51 (bdd, 1H, J=1.2 and 9Hz), 4.38 (s, 2H), 2.64 (d, 3H, J=3.3 Hz); LCMS: purity: 95%; MS (m/e):403 (MH⁺).

7.3.740 N4-(6-Chloropyridin-3-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (R920406)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(6-chloropyridin-3-yl)-5-fluoro-4-pyrimidineamine gaveN4-(6-chloropyridin-3-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.72 (s, 1H), 9.38 (s, 1H), 8.93 (t, 1H, J=3.0 Hz),8.28 (m, 1H), 8.18 (d. 1H, J=3.6 Hz), 7.95 (m, 1H), 7.45 (d, 1H, J=8.7Hz), 7.39 (m, 1H), 7.21 (m, 1H), 7.14 (t, 1H, J=4.8 Hz), 6.50 (bdd, 1H,J=7.8 Hz), 4.4 (s, 2H, 2.63 (d, 3H); LCMS: purity: 100%; MS (m/e): 403(MH⁺).

7.3.7415-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(4-methylpyridin-2-yl)-2,4-pyrimidinediamine(R927016)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(4-methylpyridin-2-yl)-4-pyrimidineamine gave5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(4-methylpyridin-2-yl)-2,4-pyrimidinediamine.LCMS: purity: 95%; MS (m/e): 383 (MH⁺).

7.3.7425-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine(R920407)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(3-trifluoromethylphenyl)-4-pyrimidineamine gave5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.835 (bs, 1H), 9.54 (bs, 1H), 8.20 (d, 1H, J=3.6Hz), 7.94 (m, 2H), 7.78 (bs, 1H), 7.43 (t, 1H, J=8.4 Hz), 7.25 (m, 2H),7.15 (t, 1H, J=7.5 Hz), 7.03 (bd, 1H, J=9.3 Hz), 6.55 (bd, 1H, J=7.5Hz), 4.36 (s, 2H), 2.63 (d, 3H, J=4.5 Hz); LCMS: purity: 91%; MS (m/e):452 (MH⁺).

7.3.743N4-(3,4-Difluoromethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R920408)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineaminegaveN4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.91 (bs, 1H), 9.64 (bs, 1H), 8.19 (d, 1H, J=3.9Hz), 8.03 (s, 1H), 7.96 (bd, 1H, J=4.8 Hz), 7.46 (m, 1H), 7.36 (d, 1H,J=8.7 Hz), 7.27 (bs, 1H), 7.17 (m, 2H), 6.57 (bdd, 1H, J=7.2 Hz), 4.36(s, 1H), 2.62 (d, 3H, J=4.5 Hz); LCMS: purity: 96%; MS (m/e): 448 (MH⁺).

7.3.744N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R920410)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineaminegaveN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.08 (d, 1H, J=5.4 Hz), 7.99 (d, 1H, J=3.6 Hz), 7.67(dd, 1H, J=2.4 and 9.0 Hz), 7.40 (m, 3H), 7.06 (m, 2H), 6.92 (dd, 1H,J=2.4 and 8.4 Hz), 4.44 (s, 2H), 2.80 (s, 3H); ¹⁹F NMR (CD₃OD): −16973and −45983; LCMS: purity: 96%; MS (m/e): 486 (MH⁺).

7.3.745 N4-(4-Ethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R926827)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(4-ethoxyphenyl)-5-fluoro-4-pyrimidineamine gaveN4-(4-ethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 96%; MS: 412 (MH⁺).

7.3.746N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-methoxy-3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926828)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-amino-6-methoxyphenoxyacetamide with2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[4-methoxy-3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.83 (s, 1H), 7.80 (d, 1H, J=4.2 Hz), 7.30 (d, 1H, 2.4Hz), 7.23 (d, 1H, J=2.4 Hz), 7.06 (m, 2H), 6.90 (d, 1H, J=5.7 Hz), 6.73(d, 1H, J=5.2 Hz), 4.32 (s, 2H), 4.22 (s, 4H), 3.86 (s, 3H), 2.83 (s,3H); LCMS: purity: 97%; MS (m/e): 455 (MH⁺).

7.3.7475-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-methoxy-3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926829)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-amino-4-methoxyphenoxyacetamide with2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-methoxy-3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.86 (d, 1H, J=4.2 Hz), 7.35 (d, 1H, J=2.4 Hz), 7.19(m, 1H), 7.12 (m, 3H), 6.93 (d, 1H, J=8.7 Hz), 6.52 (m, 1H), 4.37 (s,2H), 3.85 (s, 3H), 2.82 (s, 3H); ¹⁹F NMR (CD₃OD): −47650; LCMS: purity:100%; MS: 414 (MH⁺).

7.3.748N4-(3-Chlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926832)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of 3 N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(3-chlorophenyl)-5-fluoro-4-pyrimidineamine gaveN4-(3-chlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.12 (s, 1H), 9.93 (s, 1H), 8.27 (d, 1H, J=4.2 Hz),7.98 (d, 1H, J=4.9 Hz), 7.85 (s, 1H), 7.73 (d, 1H, J=8.1 Hz), 7.35 (t,1H, J=8.4 Hz), 7.19 (m, 3H), 6.62 (m, 1H), 4.36 (s, 2H), 2.63 (d, 3H,J=4.2 Hz); LCMS: purity: 95%; MS: 402 (MH⁺).

7.3.7495-Fluoro-N4-(3-methoxy-5-trifluoromethylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926833)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(3-methoxy-5-trifluoromethylphenyl)-4-pyrimidineaminegave5-fluoro-N4-(3-methoxy-5-trifluoromethylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 95%; MS (m/e): 466 (MH⁺).

7.3.750 5-Fluoro-N4-(3-hydroxy-4-methoxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R926834)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(3-hydroxy-4-methoxyphenyl)-4-pyrimidineamine gave5-fluoro-N4-(3-hydroxy-4-methoxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.70 (bs, 2H), 8.12 (d, 1H, J=4.8 Hz), 7.96 (m, 1H),7.12 (m, 5H), 6.85 (d, 1H, J=8.7 Hz), 6.57 (bd, 1H, J=8.1 Hz), 4.35 (s,2H), 3.74 (s, 3H), 2.63 (d, 3H, J=4.5 Hz); LCMS: purity: 99%; MS (m/e):414 (MH⁺).

7.3.7515-Fluoro-N4-(4-methoxy-3-trifluoromethylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926835)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(4-methoxy-3-trifluoromethylphenyl)-4-pyrimidineaminegave5-fluoro-N4-(4-methoxy-3-trifluoromethylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.9 Bs, 1H), 9.62 (bs, 1H), 8.17 (d, 1H, J=4.2 Hz),8.04 (bdd, 1H, J=7.2 Hz), 7.82 (t, 1H, 2.7 Hz), 7.18 (m, 3H), 7.11 (t,1H, J=8.1 Hz), 6.55 (bd, 1H, J=6.9 Hz); 4.33 (s, 2H), 3.86 (s, 3H), 2.61(d, 3H, J=4.0 Hz); LCMS: purity: 93%; MS: 466 (MH⁺).

7.3.7525-Fluoro-N4-(4-fluoro-3-trifluoromethylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926838)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(4-fluoro-3-trifluoromethylphenyl)-4-pyrimidineaminegave5-fluoro-N4-(4-fluoro-3-trifluoromethylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.80 (s, 1H), 9.44 (s, 1H), 8.25 (m, 1H), 8.18 (d,1H, J=3.9 Hz), 8.00 (m, 1H), 7.97 (m, 1H), 7.47 (t, 1H, J=9.6 Hz), 7.26(s, 1H), 7.21 (m, 1H), 7.11 (t, 1H, J=8.4 Hz), 6.51 (bd, 1H, J=9.9 Hz),4.34 (s, 2H), 2.62 (d, 3H, J=4.8 Hz); LCMS: purity: 88%; MS: 454 (MH⁺).

7.3.753N4-(3-Chloro-4-methylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926839)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(3-chloro-4-methylphenyl)-4-pyrimidineamine gaveN4-(3-chloro-4-methylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.69 (s, 1H), 9.52 (s, 1H), 8.16 (d, 1H, J=4.2 Hz),7.96 (bs, 1H), 7.81 (d, 1H, J=2.1 Hz), 7.67 (bd, 1H, J=8.4 Hz), 7.26 (m,3H), 7.15 (t, 1H, J=8.1 Hz), 6.54 (bd, 1H, J=7.2 Hz), 4.34 (s, 2H), 2.63(d, 3H, J=4.2 Hz), 2.27 (s, 3H); LCMS: purity: 80%; MS (m/e): 415 (M⁺).

7.3.754 N4-(2-Chloro-5-methylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R926840)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(2-chloro-5-methylphenyl)-4-pyrimidineamine gaveN4-(2-chloro-5-methylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.80 (bs, 2H), 8.21 (d, 1H, J=4.8 Hz), 7.92 (d, 1H,J=4.8 Hz), 7.46 (m, 1H), 7.31 (m, 2H), 7.04 (m, 2H), 6.53 (bd, 1H, J=8.1Hz), 4.30 (s, 1H), 2.18 (s, 3H); LCMS: purity: 93%; MS (m/e): 416 (MH⁺).

7.3.755 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-isopropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R926830)

The reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(ethoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewith isopropylamine (5 equivalents) in the presence ofdiisopropylethylamine (5 equivalents) in MeOH in a sealed tube at 80° C.for 24 hours gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-isopropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.15 (s, 1H), 8.04 (d, 1H, J=4.2 Hz), 7.77 (d, 1H,J=7.5 Hz), 7.28 (m, 4H), 7.08 (t, 1H, J=8.1 Hz), 6.78 (d, 1H, J=8.7 Hz),6.45 (dd, 1H, J=1.8 and 7.8 Hz), 4.30 (s, 2H), 4.20 (s, 4H), 3.92 (m,1H), 1.06 (d, 6H, J=6.6 Hz); LCMS: purity: 95%; MS (m/e): 454 (MH⁺).

7.3.756N2-[3-(N-Cyclopropylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926848)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-isopropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(ethoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewith cyclopropylamine gave5-fluoro-N4-(3,4-ethylenedioxyphenyl)-N2-[3-(N-cyclopropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.17 (bs, 2H), 8.05 (m, 2H), 7.27 (m, 4H), 7.08 (t,1H, J=8.1 Hz), 7.67 (d, 1H, J=8.7 Hz), 6.42 (dd, 1H, J=2.4 and 8.1 Hz),4.3 (s, 2H), 4.2 (bs, 4H), 2.65 (m, 1H), 0.6 (m, 2H), 0.45 (m, 2H);LCMS: purity: 91%; MS (m/e): 452 (MH⁺).

7.3.757 N4-(4-Cyano-3-methylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R926851)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(4-cyano-3-methylphenyl)-4-pyrimidineamine gaveN4-(4-cyano-3-methylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.7 (s, 1H), 9.40 (s, 1H), 8.2 (s, 1H), 8.00-7.50(m, 3H), 7.40-7.00 (m, 3H), 6.50 (bm, 1H), 4.35 (s, 2H), 2.60 (s, 3H),2.35 (s, 3H); LCMS: purity: 91%; MS (m/e): 407 (MH⁺).

7.3.7585-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[3-(tetrazol-5-yl)phenyl]-2,4-pyrimidinediamine(R926855)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine gave5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[3-(tetrazol-5-yl)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.04 (bs, 1H), 9.65 (bs, 1H), 8.35 (s, 1H), 8.23(d, 1H, J=3.9 Hz), 8.00 (bd, 1H, J=6.6 Hz), 7.91 (bd, J=3.6 Hz), 7.77(d, 1H, J=8.1 Hz), 7.57 (t, 1H, J=8.1 Hz), 7.23 (m, 2H), 6.95 (t, 1H,J=8.4 Hz), 6.46 (bdd, 1H, J=1.8 and 8.1 Hz), 4.22 (s, 2H), 2.62 (d, 3H,4.2 Hz); LCMS: purity: 83%; MS (m/e): 436 (MH⁺).

7.3.7595-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(N-methylphthalimido-4-yl)-2,4-pyrimidinediamine(R926856)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(N-methylphthalimido-4-yl)-4-pyrimidineamine gave5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(N-methylphthalimido-4-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.95 (s, 1H), 9.44 (s, 1H), 8.29 (m, 1H), 8.25 (m,1H), 8.18 (d, 1H, J=1.8 Hz), 7.88 (bd, 1H, J=4.5 Hz), 7.75 (d, 1H, J=6.6Hz), 7.38 (bs, 1H), 7.22 (bd, 1H, J=8.1 Hz), 7.14 (t, 1H, J=7.8 Hz),6.50 (dd, 1H, J=1.8 and 9.0 Hz), 4.28 (s, 2H), 2.99 (s, 3H), 2.60 (d,3H, J=4.5 Hz); LCMS: purity: 92%; MS (m/e): 451 (MH⁺).

7.3.760N4-(2,5-Dimethoxy-4-chlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926859)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide withN4-(2,5-dimethoxy-4-chlorophenyl)-2-chloro-5-fluoro-4-pyrimidineaminegaveN4-(2,5-dimethoxy-4-chlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.05 (d, 1H, J=5.4 Hz), 7.29 (s, 1H), 7.24 (t, 1H,J=8.1 Hz), 7.18 (s, 1H), 7.02 (t, 1H, J=2.1 Hz), 6.92 (dd, 1H, J=1.8 and8.1 Hz), 6.83 (dd, 1H, J=2.4 and 8.4 Hz), 4.29 (s, 2H), 3.81 (s, 3H),3.59 (s, 3H), 2.81 (s, 3H); LCMS: purity: 96%; MS (m/e): 460 (MH)—; 462(MH⁻).

7.3.761 5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3-methoxycarbonyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine(R926862)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(3-methoxycarbonyl-5-trifluoromethylphenyl)-4-pyrimidineaminegave5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3-methoxycarbonyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.95 (s, 1H), 9.41 (s, 1H), 8.57 (s, 1H), 8.33 (s,1H), 8.23 (d, 1H, J=3 Hz), 7.83 (s and d, 2H), 7.22 (m, 2H), 7.02 (t,1H, J=8.7 Hz), 6.48 (1H, J=2.4 and 7.5 Hz), 4.27 (s, 2H), 3.80 (s, 3H),2.60 (d, 3H, J=4.8 Hz); ¹⁹F NMR (DMSO-d6): −17446; LCMS: purity: 94%; MS(m/z): 494 (MH⁺).

7.3.762 5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl]-2,4-pyrimidinediamine(R926870)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl]-4-pyrimidineaminegave5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl]-2,4-pyrimidinediamine.LCMS: purity: 86%; MS (m/e): 512 (MH⁺).

7.3.763N4-[3-(2-(3-Chlorophenyl)-1,3,4-oxadiazol-5-yl)phenyl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926871)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-[3-(2-(3-chlorophenyl)-1,3,4-oxadiazol-5-yl)phenyl]-4-pyrimidineaminegaveN4-[3-(2-(3-chlorophenyl)-1,3,4-oxadiazol-5-yl)phenyl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 100%; MS (m/e): 546 (MH⁺).

7.3.764 5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[4-trifluoromethoxyphenyl]-2,4-pyrimidinediamine (R926879)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(4-trifluoromethoxyphenyl)-4-pyrimidineamine gave5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[4-trifluoromethoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.05 (bs, 1H), 9.74 (bd, 1H, J=1.5 Hz), 8.22 (d,1H, J=4.2 Hz), 7.99 (bd, 1H, J=4.5 Hz), 7.86 (m, 2H), 7.32 (d, 2H, J=8.1Hz), 7.26 (s, 1H), 7.16 (m, 2H), 6.58 (m, 1H), 4.36 (s, 2H), 2.65 (bd,3H); LCMS: purity: 92%; MS (m/e): 452 (MH⁺).

7.3.765 5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[4-trifluoromethylphenyl]-2,4-pyrimidinediamine (R926880)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(4-trifluoromethylphenyl)-4-pyrimidineamine gave5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[4-trifluoromethylphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.10 (bs, 1H), 9.72 (d, 1H, J=1.2 Hz), 8.26 (d, 1H,J=4.2 Hz), 8.00 (m, 3H), 7.65 (d, 2H, J=8.1 Hz), 7.31 (bs, 1H), 7.17 (d,2H, J=5.4 Hz), 6.59 (m, 1H), 4.36 (s, 2H), 2.62 (d, 3H, J=4.8 Hz); LCMS:purity: 92%; MS (m/e): 436 (MH⁺).

7.3.766N4-(4-Chloro-3-trifluoromethylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R926881)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(4-chloro-3-trifluoromethylphenyl)-5-fluoro-4-pyrimidineaminegaveN4-(4-chloro-3-trifluoromethylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.20 (bs, 1H), 9.81 (bs, 1H), 8.28 (d, 1H, J=3.9Hz), 8.23 (bdd, 1H, J=8.7 Hz), 8.11 (d, 1H, J=2.4 Hz), 7.98 (bd, 1H,J=4.5 Hz), 7.65 (d, 1H, J=8.7 Hz), 7.17 (m, 3H), 6.59 (m, 1H), 4.35 (s,2H), 2.63 (d, 3H, J=4.2 Hz); LCMS: purity: 87%; MS (m/e): 470 (MH⁺).

7.3.7675-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-N4-(quinolin-6-yl)-2,4-pyrimidinediamine(R926883)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of 3 N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(quinolin-6-yl)-4-pyrimidineamine gave5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-N4-(quinolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.17 (bs, 1H), 9.83 (s, 1H), 8.24 (d, 1H, J=4.8Hz), 8.17 (m, 1H), 7.94 (m, 2H), 7.86 (m, 1H), 7.39 (d, 1H, J=9.3 Hz),7.25 (s, 1H), 7.16 (m, 2H), 6.60 (m, 1H), 6.50 (d, 1H, J=9.6 Hz), 4.32(s, 2H), 2.60 (d, 3H, J=3.6 Hz); LCMS: purity: 98%; MS 9m/e): 436 (MH⁺).

7.3.768 5-Fluoro-N4-(2-methoxypyridin-5-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (R926886)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(2-methoxypyridin-5-yl)-4-pyrimidineamine gave5-fluoro-N4-(2-methoxypyridin-5-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.36 (bs, 1H), 9.19 (s, 1H), 8.59 (d, 1H, J=3 Hz),8.05 (m, 3H), 7.38 (m, 1H), 7.24 (bd, 1H, J=8.1 Hz), 7.08 (t, 1H, J=8.4Hz), 6.79 (d, 1H, J=8.7 Hz), 6.46 (dd, 1H, J=2.4 and 7.8 Hz), 4.34 (s,2H), 3.82 (s, 3H), 2.63 (d, 3H, J=4.5 Hz); LCMS: purity: 95%; MS (m/e):399 (MH⁺).

7.3.7695-Fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R927023)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-4-pyrimidineaminegave5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.65 (bs, 1H), 9.45 (bs, 1H), 8.55 (s, 1H), 8.12 (d,1H, J=3.6 Hz), 7.99 (m, 2H), 7.28 (m, 1H), 7.19 (m, 2H), 7.11 (t, 1H,J=8.4 Hz), 6.81 (d, 1H, J=8.7 Hz), 6.52 (m, 2H), 4.35 (s, 2H), 4.23 (t,2H, J=5.1 Hz), 3.69 (t, 2H, J=4.5 Hz), 2.63 (d, 3H, J=2.7 Hz); LCMS:purity: 95%; MS (m/e): 429 (MH⁺).

7.3.770N4-(2,6-Dimethoxypyridin-3-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R920404)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(2,6-dimethoxypyridin-3-yl]-5-fluoro-4-pyrimidineamine gaveN4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.05 (d, 1H, J=1.8 Hz), 8.62 (s, 1H), 8.01 (d, 1H,J=3.6 Hz), 7.91 (bd, 1H, J=4.8 Hz), 7.77 (m, 1H), 7.18 (m, 2H), 6.96 (t,1H, J=8.1 Hz), 6.40 (d, 2H, J=8.1 Hz), 4.29 (s, 2H), 3.86 (s, 3H), 3.85(s, 3H), 2.63 (d, 3H, J=4.5 Hz); LCMS: purity: 86%; MS (m/e): 429 (MH⁺).

7.3.771N4-(4-Chloro-3-methoxyphenyl))-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R927042)

In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(4-chloro-3-methoxyphenyl)-5-fluoro-4-pyrimidineamine gaveN4-(4-chloro-3-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.89 (bs, 1H), 9.66 (bs, 1H), 8.20 (d, 1H, J=4.2Hz), 7.95 (bd, 1H), 7.48 (m, 2H), 7.33 (d, 1H, J=9.1 Hz), 7.26 (bs, 1H),7.17 (m, 2H), 6.57 (bd, 1H, J=7.8 Hz), 4.34 (s, 2H), 3.72 (s, 3H), 2.62(d, 3H); LCMS: purity: 97%; MS (m/e): 432 (MH⁺).

7.3.772N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R920411)

A solution of2-chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamine(1.1 equivalents) and 3-hydroxyaniline (1 equivalent) in a sealed tubewas heated at 100° C. for 24 hours. The resulting solution was dilutedwith EtOAc and the solid obtained was filtered, washed with a mixture ofEtOAc:n-hexanes (1:1; v/v), dried and analyzed to giveN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine.¹H NMR (CD₃OD): δ 8.02 (d, 1H, J=5.1 Hz), 7.98 (d, 1H, J=3.0 Hz), 7.72(dd, 1H, J=3.0 and 9.3 Hz), 7.42 (dd, 1H, J=1.2 and 9.0 Hz), 7.22 (t,1H, J=8.4 Hz), 6.85 (m, 2H), 6.73 (dd, 1H, J=2.4 and 8.7 Hz); ¹⁹F NMR(CD₃OD): −16967 and −46027; LCMS: purity: 97%; MS (m/e): 415 (MH⁺).

7.3.7735-Fluoro-N2-(3-hydroxyphenyl)-N4-[3-(3-phenyl-1,3,4-oxadiazol-5-yl)phenyl]-2,4-pyrimidinediamine(R926866)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 3-hydroxyaniline with2-chloro-5-fluoro-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl]-4-pyrimidineaminegave5-fluoro-N2-(3-hydroxyphenyl)-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.72 (bs, 1H), 7.96 (bd, 3H), 7.85 (m, 2H), 7.56 (m,4H), 7.14 (d, 1H, J=2.1 Hz), 6.91 (m, 2H), 6.28 (dd, 1H, J=1.8 and 6.9Hz); LCMS: purity: 80%; MS (m/e): 441 (MH⁺).

7.3.774N4-(3,4-Difluoromethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926794)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 3-hydroxyaniline with2-chloro-N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineaminegaveN4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: purity: 85%; MS (m/e): 377 (MH⁺).

7.3.7755-Fluoro-N2-(3-hydroxyphenyl)-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine(R926885)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 3-hydroxyaniline with2-chloro-5-fluoro-N4-(3-trifluoromethoxyphenyl)-4-pyrimidineamine gave5-fluoro-N2-(3-hydroxyphenyl)-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.99 (bs, 1H), 9.61 (bs, 1H), 8.21 (d, 1H, J=4.2Hz), 7.93 (bd, 1H, J=7.5 Hz), 7.78 (s, 1H), 7.43 (t, 1H, J=8.4 Hz), 7.03(m, 4H), 6.43 (m, 1H); ¹⁹F NMR (DMSO-d6): −16097; LCMS: purity: 85%; MS(m/e): 381 (MH⁺).

7.3.776N4-(2,6-Dimethoxypyridin-3-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926887)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 3-hydroxyaniline with2-chloro-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-4-pyrimidineamine gaveN4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.98 (bs, 2H), 8.20 (d, 1H, J=5.4 Hz), 7.72 9m, 1H),6.90 (t, 1H, J=7.8 Hz), 6.81 (m, 2H), 6.42 (m, 2H), 3.88 (s, 3H), 3.86(s, 3H); LCMS: purity: 94%; MS (m/e): 358 (MH⁺).

7.3.7775-Fluoro-N2-(3-hydroxyphenyl)-N4-(5-methylpyridin-2-yl)-2,4-pyrimidinediamine(R927017)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 3-hydroxyaniline with2-chloro-5-fluoro-N4-(5-methylpyridin-2-yl)-4-pyrimidineamine gave5-fluoro-N2-(3-hydroxyphenyl)-N4-(5-methylpyridin-2-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 11.39 (bs, 1H), 10.59 (bs, 1H), 8.58 (s, 1H0, 8.41(d, 1H, J=3 Hz), 8.12 (d, 1H, J=8.7 Hz), 7.82 (d, 1H, J=8.7 Hz), 7.29(s, 1H), 7.16 (d, 1H, J=9 Hz), 7.05 (t, 1H, J=8.4 Hz), 6.38 (dd, 1H, 1.2and 6.9 Hz); LCMS: purity: 99%; MS (m/e): 312 (MH⁺).

7.3.778N4-(6-Chloropyridin-3-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R927018)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 3-hydroxyaniline with2-chloro-N4-(6-chloropyridin-3-yl)-5-fluoro-4-pyrimidineamine gaveN4-(6-chloropyridin-3-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.10 (bs, 1H), 9.64 (bs, 1H), 8.85 (m, 1H), 8.30(m, 2H), 8.22 (d, 1H, J=4.2 Hz), 7.43 (d, 1H, J=8.7 Hz), 7.01 (m, 3H),6.42 (bd, 1H, J=8.4 Hz); LCMS: purity: 93%; MS (m/e): 332 (MH⁺).

7.3.7795-Fluoro-N2-(3-hydroxyphenyl)-N4-(quinolin-6-yl)-2,4-pyrimidinediamine(R927019)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 3-hydroxyaniline with2-chloro-5-fluoro-N4-(quinolin-6-yl)-4-pyrimidineamine gave5-fluoro-N2-(3-hydroxyphenyl)-N4-(quinolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.50 (s, 1H), 10.14 (s, 1H), 8.29 (d, 1H, J=4.8Hz), 8.14 (d, 1H, J=1.8 Hz), 7.96 (d, 1H, J=9.3 Hz), 7.83 (dd, 1H, J=2.4and 9.0 Hz), 7.40 (d, 1H, J=8.7 Hz), 7.04 (t, 1H, J=8.1 Hz), 6.93 (m,2H), 6.52 (m, 2H); LCMS: purity: 93%; MS (m/e): 365 (MH⁺).

7.3.780N4-(5-Chloropyridin-2-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R927020)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 3-hydroxyaniline with2-chloro-N4-(5-chloropyridin-2-yl)-5-fluoro-4-pyrimidineamine gaveN4-(5-chloropyridin-2-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.80 (bs, 1H), 9.77 (bs, 1H), 8.45 (bd, 1H), 8.26(d, 1H, J=3.9 Hz), 8.15 (d, 1H, J=8.7 Hz), 7.85 (dd, 1H, J=2.4 and 8.7Hz), 7.06 (m, 3H), 6.43 (bd, 1H, J=7.2 Hz); LCMS: purity: 97%; MS (m/e):332 (MH⁺).

7.3.781N4-(4-Chloro-2,5-dimethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-primidinediamine(R926860)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 3-hydroxyaniline with2-chloro-N4-(4-chloro-2,5-dimethoxyphenyl)-5-fluoro-4-pyrimidineaminegaveN4-(4-chloro-2,5-dimethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-primidinediamine.¹H NMR (CD₃OD): δ 7.96 (d, 1H, J=4.8 Hz), 7.66 (s, 1H), 7.13 (s, 1H),7.07 (t, 1H, J=8.7 Hz), 8.86 (m, 2H), 6.57 (dd, 1H, J=3.2 and 8.1 Hz),3.48 (s, 3H), 3.66 (s, 3H); ¹⁹F NMR (CD₃OD): −46968.

7.3.782N4-(4-Chlorophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine(R927026)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 5-amino-2-methoxycarbonylbenzofuran with2-chloro-N4-(4-chlorophenyl)-5-fluoro-4-pyrimidineamine gaveN4-(4-chlorophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.28 (bs, 1H), 10.18 (bs, 1H), 8.25 (d, 1H, J=4.5Hz), 7.96 (bs, 1H), 7.84 (m, 1H), 7.67 (m, 3H), 7.57 (m, 1H), 7.37 (bd,2H, J=9.0 Hz), 3.88 (s, 3H); LCMS: purity: 96%; MS (m/e): 413 (MH⁺).

7.3.783N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine(R927027)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 5-amino-2-methoxycarbonylbenzofuran with2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine gaveN4-(3,4-dichlorophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.70 (bs, 1H), 9.50 (bs, 1H), 8.20 (d, 1H, J=4.5Hz), 8.09 (m, 1H), 7.80 (m, 3H), 7.62 (m, 2H), 7.53 (m, 1H), 7.38 (m,1H), 3.88 (s, 3H); LCMS: purity: 94%; MS (m/e): 448 (MH⁺).

7.3.7845-Fluoro-N4-(3-hydroxyphenyl)-N2-(3-methoxycarbonyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine(R926863)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3-methoxycarbonyl-5-trifluoromethylaniline gave5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-methoxycarbonyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.98 (s, 1H), 9.52 (s, 1H), 8.53 (s, 1H), 8.38 (s,1H), 8.20 (d, 1H, J=4.2 Hz), 7.69 (s, 1H), 7.27 (d, 1H, J=8.1 Hz), 7.14(s, 1H), 7.05 (t, 1H, 7.8 Hz), 6.49 (dd, 1H, J=1.8 and 8.4 Hz), 3.80 (s,3H); LCMS: purity: 82%; MS (m/e): 423 (MH⁺).

7.3.785N2-(4-Chloro-2,5-dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926857)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 4-chloro-2,5-dimethoxyaniline gaveN2-(4-chloro-2,5-dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.04 (d, 1H, J=5.4 Hz), 7.46 (s, 1H), 7.17 (m, 2H),7.03 (m, 2H), 6.72 (dd, 1H, J=1.8 and 7.8 Hz), 3.85 (s, 3H), 3.52 (s,3H); LCMS: purity: 98%; MS (m/e): 390 (MH⁺).

7.3.786N2-(3-Bromo-5-trifluorophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926846)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3-bromo-5-trifluoromethylaniline gaveN2-(3-bromo-5-trifluorophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.70 (s, 1H), 9.36 (s, 1H), 9.34 (s, 1H), 8.31 (s,1H), 8.18 (d, 1H, J=3.6 Hz), 8.02 (s, 1H), 7.35 (s, 1H), 7.28 (bd, 1H,J=7.2 Hz), 7.11 (t, 1H, J=8.4 Hz), 7.02 (m, 1H), 6.49 (dd, 1H, J=1.8 and7.8 Hz); LCMS: purity: 94%; MS (m/e): 442 (MH⁺).

7.3.7875-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(1H-pyrazol-3-yl)phenyl]-2,4-pyrimidinediamine(R926841)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3-(1H-pyrazol-3-yl)aniline gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(1H-pyrazol-3-yl)phenyl]-2,4-pyrimidinediamine.LCMS: purity: 84%; MS 363 (MH⁺)

7.3.7885-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(tetrazol-5-yl)phenyl]-2,4-pyrimidinediamine(R926842)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3-(tetrazol-5-yl)aniline gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(tetrazol-5-yl)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.05 (bs, 1H), 9.80 (bs, 1H), 8.27 (s, 1H), 8.23(d, 1H, J=3.3 Hz), 7.86 (d, 1H, J=8.1 Hz) 7.65 (d, 1H, J=6.9 Hz), 7.44(t, 1H, J=7.5 Hz), 7.19 (m, 2H), 6.93 (t, 1H, J=7.5 Hz), 6.49 (dd, 1H,J=2.4 and 8.1 Hz); LCMS: purity: 89%; MS (m/e): 364 (MH⁺).

7.3.7895-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine(R926831)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3-(1,3-oxazol-5-yl)aniline gave5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine.LCMS: purity: 76%; MS (m/e): 364 (MH⁺).

7.3.790N2-(3-Chloro-4-trifluoromethylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinedimine(R926844)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3-chloro-4-trifluoromethoxyaniline gaveN2-(3-chloro-4-trifluoromethylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinedimine.¹H NMR (DMSO-d6): δ 9.70 (bs, 1H), 9.48 (bs, 1H), 8.15 (bd, 1H, J=3.6Hz), 8.06 (s, 1H), 7.62 (dd, 1H, J=2.4 and 9.3 Hz), 7.37 (d, 1H, J=9.0Hz), 7.20 9m, 1H), 7.11 (m, 3H), 6.53 (bd, 1H, J=8.1 Hz); LCMS: purity:93%; MS (m/e): 414 (MH⁺).

7.3.7915-Fluoro-N4-(3,4-ethylenedioxyphenyl)-N2-[3-(tetrazol-5-yl)phenyl]-2,4-pyrimidinediamine(R926843)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of2-chloro-5-fluoro-N4-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine with3-(tetrazol-5-yl)aniline gave5-fluoro-N4-(3,4-ethylenedioxyphenyl)-N2-[3-(tetrazol-5-yl)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.91 (s, 1H), 9.74 (s, 1H), 8.29 (s, 1H), 8.18 (d,1H, J=4.5 Hz), 7.76 (bdd, 1H, J=1.5 and 8.1 Hz), 7.64 (d, 1H, J=8.1 Hz),7.46 (t, 1H, J=8.1 Hz), 7.29 (m, 1H), 7.13 (dd, 1H, J=2.4 and 8.7 Hz),6.64 (d, 1H, J=8.7 Hz), 4.11 (m, 4H); LCMS: purity: 91%; MS (m/e): 407(MH⁺).

7.3.792N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(4-methoxy-2-methylphenyl)-2,4-pyrimidinediamine(R926845)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of2-chloro-5-fluoro-N4-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine with4-methoxy-2-methylaniline gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-methoxy-2-methylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.30 (bs, 1H), 9.10 (bs, 1H), 8.22 (d, 1H, J=5.1Hz), 7.55 (m, 1H), 7.15 (m, 1H), 7.07 (m, 1H), 6.92 (m, 2H), 6.82 (d,1H, J=8.7 Hz), 4.22 (bs, 4H), 3.80 (s, 3H), 2.15 (s, 3H); LCMS: purity:94%; MS (m/e): 383 (MH⁺).

7.3.793N2-[5-(N-Aminocarbonylmethylene-2-oxo-1,3-oxazol-3(2H)-yl)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrmidinediamine(R926847)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of2-chloro-5-fluoro-N4-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine with2-[5-amino-2-oxo-1,3-benzoxazol-3(2H)-yl)acetamide gaveN2-[5-(N-aminocarbonylmethylene-2-oxo-1,3-oxazol-3(2H)-yl)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrmidinediamine.¹H NMR (CD₃OD): δ 7.95 (d, 1H, J=8.4 Hz), 7.32 (dd, 1H, J=2.4 and 8.1Hz), 7.24 (d, 1H, J=2.4 Hz), 7.19 (m, 2H), 6.95 (dd, 1H, J=2.7 and 9Hz), 6.80 (d, 1H, J=9 Hz), 4.51 (s, 2H), 4.21 (m, 4H).

7.3.794N2-[3-(2-Ethoxycarbonylmethylene-1,3,4-oxadiazol-5-yl)phenyl-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926874)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3-(2-ethoxycarbonylmethylene-1,3,4-oxadiazol-5-yl)aniline gaveN2-[3-(2-ethoxycarbonylmethylene-1,3,4-oxadiazol-5-yl)phenyl-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.52 (s, 1H), 9.31 (s, 1H), 9.28 (s, 1H), 8.30 (s,1H), 8.12 (d, 1H, J=3.6 Hz), 8.00 (m, 1H), 7.49 (d, 1H, J=7.5 Hz), 7.42(d, 1H, J=8.4 Hz), 7.30 (m, 1H), 7.12 (bs, 1H), 7.03 (t, 1H, J=8.1 Hz),6.46 (m, 1H), 4.21 (s, 2H), 4.15 (q, 2H, J=6.9 Hz), 1.19 (t, 3H, J=7.2Hz); LCMS: purity: 90%; MS (m/e): 451 (MH⁺).

7.3.795 N2,N4-Bis(3-boronylphenyl)-5-fluoro-2,4-pyrimidinediamine(R926836)

A mixture of 2,4-dichloro-5-fluoro-pyrimidine (1 equivalents) and3-aminophenylboronic acid (3 equivalents) in MeOH was heated in a sealedtube at 100° C. for 24 hours. The resulting mixture was cooled to roomtemperature, acidified with 2N HCl and the solid obtained was filtered,washed with water, dried and analyzed to giveN2,N4-sis(3-boronylphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(DMSO-d6): δ 10.40 (s, 1H), 10.07 (s, 1H), 8.25 (d, 8.4 Hz), 7.85 (s,1H), 7.73 (d, 1H, J=7.5 Hz), 7.63 (bt, 3H), 7.48 (d, 1H, J=6.9 Hz), 7.30(t, 1H, J=8.4 Hz), 7.12 (t, 1H, J=2.5 Hz); LCMS: purity: 85%; MS (m/e):368 (MH⁺).

7.3.796N2-(3-Boronylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926837)

In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of2-chloro-5-fluoro-N4-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine with3-aminophenylboronic acid gaveN2-(3-boronylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 99%; MS (m/e): 383 (MH⁺).

7.3.797(+)-N4-(3,4-Difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine(R927030)

A mixture of equivalent amount of2-chloro-N4-(3,4-difluorophenyl)-5-fluoro-4-pyrimidineamine and(±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran in MeOH was shakenin a sealed tube at 80° C. for 48 h, cooled to room temperature anddiluted with a mixture of n-hexanes:EtOAc (1:1; v/v). The resultingsolid formed was filtered, washed with a mixture of EtOAc:n-hexanes(1:1; v/v), dried and analyzed to give(+)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.21 (bs, 1H), 9.80 (bs, 1H), 8.20 (d, 1H, J=4.8Hz), 7.94 (bs, 1H), 7.43 (m, 3H0, 7.15 (bd, 1H, J=8.4 Hz), 6.81 (d, 1H,J=8.1 Hz), 5.35 (dd, 1H, J=6.0 and 6.3 Hz), 3.69 (s, 3H), 3.52 (dd, 1H,J=10.5), 3.22 (dd, 1H, J=9.0 and 6.0 Hz); LCMS: purity: 99%; MS (m/e):417 (MH⁺).

7.3.798(+)-N4-(4-Chlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine(R927024)

In like manner to the preparation of(+)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine,the reaction of (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran with2-chloro-N4-(4-chlorophenyl)-5-fluoro-4-pyrimidineamine gave(+)-N4-(4-chlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.29 (bs, 1H), 9.89 (bs, 1H), 8.21 (d, 1H, J=4.8Hz), 7.69 (m, 2H), 7.38 (m, 3H), 7.13 (bd, 1H, J=8.1 Hz), 6.83 (d, 1H,J=8.4 Hz), 5.36 (dd, 1H, J=6.3 and 5.7 Hz), 3.70 (s, 3H), 3.52 (dd, 1H,J=10.5 Hz), 3.20 (dd, 1H, J=5.4 and 5.7 Hz); LCMS: purity: 98%; MS(m/e): 415 (MH⁺).

7.3.799(+)-N4-(3,4-Dichlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine(R927031)

In like manner to the preparation of(+)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine,the reaction of (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran with2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine gave(+)-N4-(3,4-dichlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.13 (bs, 1H), 9.70 (bs, 1H), 8.21 (d, 1H, J=4.8Hz), 8.04 (d, 1H, J=2.4 Hz), 7.68 (m, 1H), 7.54 (d, 1H, J=9.0 Hz), 7.37(bs, 1H), 7.19 (m, 1H), 6.80 (d, 1H, J=8.7 Hz), 5.35 (dd, 1H, J=6.6 Hz),3.69 (s, 3H), 3.53 (dd, 1H, J=10.5 and 11.1 Hz), 3.21 (dd, 1H, J=6.0Hz); LCMS: purity: 100%; MS (m/e): 450 (MH⁺).

7.3.800(+)-N2-(2,3-Dihydro-2-methoxycarbonylbenzofuran-5-yl)-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-2,4-pyrimidinediamine(R927032)

In like manner to the preparation of(+)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine,the reaction of (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran with2-chloro-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-4-pyrimidineamine gave(+)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.03 (bs, 2H), 8.18 (d, 1H, J=4.8 Hz), 7.68 (bd,1H, J=8.1 Hz), 7.27 (bs, 1H), 6.98 (bd, 1H, J=8.1 Hz), 6.69 (d, 1H,J=8.7 Hz), 6.44 (d, 1H, J=8.1 Hz), 5.33 (dd, 1H, J=5.7 Hz), 3.88 (s,3H), 3.86 (s, 3H), 3.69 (s, 3H), 3.42 (dd, 1H, J=10.8 and 11.1 Hz), 3.10(dd, 1H, J=6.3 and 6.6 Hz); LCMS: purity: 99%; MS (m/e): 442 (MH⁺).

7.3.801(+)-N2-(2,3-Dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-5-fluoro-2,4-pyrimidinediamine(R927025)

In like manner to the preparation of(+)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine,the reaction of (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran with2-chloro-5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-4-pyrimidineaminegave(+)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.10 (bs, 1H), 9.70 (bs, 1H), 8.46 (m, 1H), 8.13(d, 1H, J=4.8 Hz), 7.92 (m, 1H), 7.41 (bs, 1H), 7.12 (bdd, 1H, J=8.4Hz), 6.79 (m, 2H), 5.35 (dd, 1H, J=5.7 and 6.0 Hz), 4.24 (t, 2H, J=5.1Hz), 3.70 (s, 3H), 3.69 (t, 2H, J=5.1 Hz), 3.52 (dd, 1H, J=11.1 Hz),3.24 (dd, 1H, J=6.6 Hz); LCMS: purity: 92%; MS (m/e): 442 (MH⁺).

7.3.802(+)-N2-(2,3-Dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-N4-(3-trifluorophenyl)-2,4-pyrimidinediamine(R927028)

In like manner to the preparation of(+)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine,the reaction of (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran with2-chloro-5-fluoro-N4-(3-trifluorophenyl)-4-pyrimidineamine gave(+)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-N4-(3-trifluorophenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.32 (bs, 1H), 9.90 (bs, 1H), 8.23 (d, 1H, J=4.8Hz), 7.80 (bd, 1H, J=6.9 Hz), 7.73 (bs, 1H), 7.43 (t, 1H, J=8.1 Hz),7.36 (bs, 1H), 7.16 (m, 2H), 6.79 (d, 1H, J=8.1 Hz), 5.33 (dd, 1H, J=6.0and 6.6 Hz), 3.69 (s, 3H), 3.51 (dd, 1H, J=10.5 Hz), 3.20 (dd, 1H, J=6.0Hz); LCMS: purity: 98%; MS (m/e): 465 (MH⁺).

7.3.803(+)-N2-(2,3-Dihydro-2-methoxycarbonylbenzofuran-5-yl)-N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R927029)

In like manner to the preparation of(+)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine,the reaction of (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran with2-chloro-N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineaminegave(+)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 10.36 (bs, 1H), 9.93 (bs, 1H), 8.22 (d, 1H, J=4.8Hz), 7.91 (bs, 1H), 7.38 (m, 3H), 7.15 9bd, 1H, J=8.7 Hz), 6.79 (d, 1H,J=6.0 Hz), 5.33 (dd, 1H, J=6.3 and 6.6 Hz), 3.69 (s, 3H), 3.50 (dd, 1H,J=10.5 and 10.8 Hz), 3.22 (dd, 1H, J=6.0 Hz); LCMS: purity: 100%; MS(m/e): 461 (MH⁺). Esters were transformed to amides allowing to thescheme illustrated below:

7.3.804(+)-N4-(3,4-Difluorophenyl)-5-fluoro-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R927035)

A mixture of(+)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine,methylamine Hydrogen Chloride (5 equivalents) and diisopropylethylamine(5 equivalents) in MeOH was shaken in a sealed tube at 80° C. for 24 h.The resulting solution was diluted with water and the precipitateobtained was filtered, washed with water, dried and analyzed to afford(+)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.46 (s, 1H), 9.07 (s, 1H), 8.05 (m, 3H), 7.48 (m,2H), 7.35 (m, 1H), 7.22 (m, 1H), 6.72 (d, 1H, J=8.1 Hz), 5.07 (dd, 1H,J=6.6 and 6.3 Hz), 3.40 (dd, 1H), 3.15 (dd, 1H), 2.60 (d, 3H, J=4.5 Hz);LCMS: purity: 98%; MS (m/e): 416 (MH⁺).

7.3.805(+)-N4-(4-Chlorophenyl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine(R927036)

In like manner to the preparation of(+)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2-(N-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine,the reaction of methyl amine Hydrogen Chloride with(+)-N4-(4-chlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediaminegave(+)-N4-(4-chlorophenyl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.40 (s, 1H), 9.02 (s, 1H), 8.05 (m, 2H), 7.84 (dd,2H, J=2.7 and 9.3 Hz), 7.51 (bs, 1H), 7.32 (bd, 2H, J=8.7 Hz), 7.23 (bd,1H, J=8.7 Hz), 6.72 (d, 1H, J=8.7 Hz), 5.07 (dd, 1H, J=6.0 and 6.3 Hz),3.39 (dd, 1H), 3.17 (dd, 1H), 2.60 (d, 3H, J=4.8 Hz); LCMS: purity: 99%;MS (m/e): 414 (MH⁺).

7.3.806(+)-N4-(3,4-Dichlorophenyl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine(R927037)

In like manner to the preparation of(+)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2-(N-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine,the reaction of methyl amine Hydrogen Chloride with(+)-N4-(3,4-dichlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediaminegave(+)-N4-(3,4-dichlorophenyl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.52 (s, 1H), 9.09 (s, 1H), 8.08 (m, 3H), 7.76 (bd,1H, J=9.3 Hz), 7.50 (d, 1H, J=9.0 Hz), 7.43 (bs, 1H), 7.24 (bd, 1H,J=8.7 Hz), 6.73 (d, 1H, J=8.1 Hz), 5.07 (dd, 1H, J=6.3 and 6.6 Hz), 3.39(dd, 1H, J=10.5 Hz), 3.15 (dd, 1H, J=6.3 Hz), 2.60 (d, 3H, J=4.8 Hz);LCMS: purity: 99%; MS (m/e): 450 (MH⁺).

7.3.807(+)-N4-(2,6-Dimethoxypyridin-3-yl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine(R927038)

In like manner to the preparation of(+)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2-(N-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine,the reaction of methyl amine Hydrogen Chloride with(+)-N4-(2,6-dimethoxypyridin-3-yl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediaminegave(+)-N4-(2,6-dimethoxypyridin-3-yl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.98 (d, 1H, J=8.1 Hz), 7.81 (d, 1H, J=3.6 Hz), 7.39(bd, 1H, J=2.4 Hz), 7.06 (dd, 1H, J=2.4 and 8.7 Hz), 6.72 (d, 1H, J=8.1Hz), 6.31 (d, 1H, J=8.7 Hz), 5.07 (dd, 1H, J=6.3 Hz), 3.96 (s, 3H), 3.93(s, 3H), 3.46 (dd, 1H, J=7.8 and 10.5 Hz), 3.19 (dd, 1H, J=5.7 and 6.3Hz), 2.77 (d, 3H, J=4.8 Hz); LCMS: purity: 98%; MS (m/e): 441 (MH⁺).

7.3.808(+)-N2-[2,3-Dihydro-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-2,4-pyrimidinediamine(R927039)

In like manner to the preparation of(+)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2-(N-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine,the reaction of methyl amine Hydrogen Chloride with(+)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-2,4-pyrimidinediaminegave(±)-5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-N2-[2-(N-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.26 (s, 1H), 8.99 (s, 1H), 8.50 (bd, 1H, J=3.0 Hz),8.02 (bd, 2H, J=3.6 Hz), 7.94 (dd, 2H, J=2.7 and 5.1 Hz), 7.52 (bs, 1H),7.20 (bd, 1H, J=8.7 Hz), 6.78 (d, 1H, J=8.7 Hz), 6.67 (d, 1H, J=8.7 Hz),5.05 (dd, 1H, J=6.3 and 6.6 Hz), 4.80 (t, 1H), 4.23 (t, 2H, J=5.1 Hz),3.69 (q, 2H, J=5.4 Hz), 3.40 (dd, 1H), 3.15 (dd, 1H, J=6.3 and 9.9 Hz),2.60 (d, 3H, J=4.5 Hz); LCMS: purity: 86%; MS (m/e): 441 (MH⁺).

7.3.809(+)-N2-[2,3-Dihydro-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine(R927040)

In like manner to the preparation of(+)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2-(N-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine,the reaction of methyl amine Hydrogen Chloride with(+)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediaminegave(+)-N2-[2,3-dihydro-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine.LCMS: purity: 94%; MS (m/e): 464 (MH⁺).

7.3.810(+)-N2-[2,3-Dihydro-(N-methylamino)carbonylbenzofuran-5-yl]-N4-(3,4-difluoromethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R927041)

In like manner to the preparation of(+)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2-(N-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine,the reaction of methyl amine Hydrogen Chloride with(+)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediaminegave(+)-N2-[2,3-dihydro-(N-methylamino)carbonylbenzofuran-5-yl]-N4-(3,4-difluoromethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.46 (s, 1H), 9.05 (s, 1H), 8.05 (m, 3H), 7.43 (m,2H), 7.31 (d, 1H, J=8.7 Hz), 7.23 (bd, 1H, J=7.5 Hz), 6.70 (d, 1H, J=9.0Hz), 5.04 (dd, 1H, J=6.6 Hz), 3.40 (dd, 1H), 3.14 (dd, 1H, J=5.7 and 6.6Hz), 2.60 (d, 3H, J=3.9 Hz); LCMS: purity: 94%; MS (m/e): 460 (MH⁺).

7.3.811N2-(4-Carboxymethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926238)

The reaction ofN2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith LiOH in THF:H₂O at room temperature gaveN2-(carboxymethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 8.16 (d, 1H, J=4.8 Hz), 7.37 (bd, 2H, J=9 Hz), 7.259d, 1H, J=3 Hz), 7.08 (m, 1H), 6.83 (m, 3H), 4.64 (s, 2H), 4.23 (s, 4H);LCMS: ret. time: 19.15 min.; purity: 100%; MS (m/e): 413 (MH⁺).

7.3.812N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt (R920395)

To a solution ofN4-(1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(1 equivalent) in MeOH at 0° C. was added HCl (4M, dioxane, 1.1equivalents) dropwise and shaken for 5 minutes. The resulting solutionwas diluted with EtOAc and the solid obtained was filtered washed withEtOAc, dried and analyzed to giveN4-(1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt. ¹H NMR (DMSO-d6): δ 9.80 (bs, 2H), 8.12 (d, 1H,J=4.8 Hz), 7.89 (bd, 1H, J=4.5 Hz), 7.18 (m, 3H), 8.24 (m, 2H), 6.60(bd, 2H, J=8.1 Hz), 4.36 (s, 2H), 4.10 (t, 2H, J=3.9 Hz), 3.27 (t, 2H,J=3.9 Hz), 2.62 (d, 3H, J=4.5 Hz); LCMS: purity: 98%, MS (m/e): 425(MH⁺).

7.3.813N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineTrifluoro Acetic Acid Salt (R926826)

In like manner to the synthesis ofN4-(1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminewith trifluoroacetic acid gaveN4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineTrifluoro Acetic Acid Salt. ¹H NMR (DMSO-d6): δ 9.40 (bs, 1H), 9.36 (bs,1H), 8.07 (d, 1H, J=4.2 Hz), 7.94 (bd, 1H), 7.22 (m, 4H), 7.11 (t, 1H,J=7.5 Hz), 6.79 (d, 1H, J=8.7 Hz), 6.51 (bd, 1H, J=7.5 Hz), 4.33 (s,2H), 4.21 (bs, 4H), 2.63 (d, 3H, 3.3 Hz).

7.3.8145-Fluoro-N4-[(1H)-indol-6-yl]-N2-[4-methoxy-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926752)

In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[(1H)indol-6-yl]-4-pyrimidineamine and4-methoxy-3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toproduce5-fluoro-N4-[(1H)-indol-6-yl]-N2-[4-methoxy-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.83 (d, 1H, J=3.6 Hz), 7.73 (d, 1H, J=0.9 Hz), 7.49(d, 1H, J=8.1 Hz), 7.39 (d, 1H, J=3.0 Hz), 7.20 (d, 1H, J=3.6 Hz), 7.15(dd, 1H, J=1.8 and 8.1 Hz), 7.05 (dd, 1H, J=2.1 and 8.7 Hz), 6.81 (d,1H, J=8.7 Hz), 6.41 (d, 1H, J=4.2 Hz), 4.09 (s, 2H), 3.81 (s, 3H), 2.76(s, 3H); LCMS: purity: 100%; MS (m/e): 437 (MH⁺).

7.3.8155-Fluoro-N4-(3-hydroxy-4-methylphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926753)

In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(2-hydroxy-4-methylphenyl)-4-pyrimidineamine and3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted to produce5-fluoro-N4-(3-hydroxy-4-methylphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.95 (bs, 1H), 9.83 (bs, 1H), 9.38 (bs, 1H), 8.17(d, 1H, J=4.4 Hz), 7.97 (d, 1H, J=4.8 Hz), 7.24-7.17 (m, 2H), 7.16 (d,1H, J=8.4 Hz), 7.10 (dd, 1H, J=1.8 and 8.4 Hz), 7.03 (d, 1H, J=2.4 Hz),7.00 (d, 1H, J=9.0 Hz), 6.61 (d, 1H, J=8.7 Hz), 4.34 (s, 2H), 2.63 (d,3H, J=4.5 Hz), 2.08 (s, 3H); LCMS: purity: 96%; MS (m/e): 398 (MH⁺).

7.3.8165-Fluoro-N4-(3-dihydroxyborylphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926754)

In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-dihydroxyborylphenyl)-4-pyrimidineamine and3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted to produce5-fluoro-N4-(3-dihydroxyborylphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.38 (bs, 1H), 9.22 (bs, 1H), 8.08 (d, 1H, J=3.6Hz), 8.06-7.81 (m, 4H), 7.51 (d, 1H, J=8.1 Hz), 7.33-7.28 (m, 3H), 7.06(t, 1H, J=8.1 Hz), 6.44 (dd, 1H, J=2.4 and 7.5 Hz), 4.33 (s, 2H), 2.63(d, 3H, J=4.8 Hz); LCMS: purity: 95%; MS (m/e): 412 (MH⁺).

7.3.8175-Fluoro-N4-(3-dihydroxyborylphenyl)-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926755)

In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-dihydroxyborylphenyl)-4-pyrimidineamine and3-hydroxyaniline were reacted to produce5-Fluoro-N4-(3-dihydroxyborylphenyl)-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.68 (bs, 1H), 9.35 (bs, 1H), 9.22 (bs, 1H), 8.10(d, 1H, J=3.9 Hz), 7.88-7.80 (m, 2H), 7.54 (d, 1H, J=7.2 Hz), 7.31 (t,1H, J=7.2 Hz), 7.08 (d, 1H, J=8.4 Hz), 6.98-6.93 (m, 2H), 6.35 (d, 1H,J=8.4 Hz); LCMS: purity: 96%; MS (m/e): 341 (MH⁺).

7.3.818N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-(3-hydroxyborylphenyl)-2,4-pyrimidinediamine(R926756)

In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-dihydroxyborylphenyl)-4-pyrimidineamine and3,4-ethylenedioxyaniline were reacted to produceN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-(3-hydroxyborylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.46 (bs, 1H), 9.11 (bs, 1H), 8.05 (d, 1H, J=4.2Hz), 7.95 (bs, 1H), 7.88 (s, 1H), 7.78 (d, 1H, J=7.5 Hz), 7.52 (d, 1H,J=7.5 Hz), 7.29 (t, 1H, J=7.5 Hz), 7.16 (s, 1H), 7.02 (d, 1H, J=8.7 Hz),6.65 (d, 1H, J=8.7 Hz), 3.40 (s, 4H); LCMS: purity: 98%; MS (m/e): 383(MH⁺).

7.3.8195-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926757)

In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toproduce5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.32 (s, 1H), 9.17 (s, 1H), 9.04 (s, 1H), 8.04 (d,1H, J=4.2 Hz), 7.76 (d, 1H, J=4.8 Hz), 7.32 (td, 2H, J=1.8 and 8.1 Hz),7.13-7.04 (m, 3H), 6.95 (d, 1H, J=8.4 Hz), 6.46 (dd, 1H, J=1.8 and 8.4Hz), 4.31 (s, 2H), 2.65 (d, 3H, J=4.8 Hz), 2.14 (s, 3H); LCMS: purity:99%; MS (m/e): 398 (MH⁺).

7.3.820N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926758)

In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toproduceN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.13 (bs, 1H), 9.05 (s, 1H), 8.01 (d, 1H, J=4.2 Hz),7.76 (d, 1H, J=4.8 Hz), 7.32 (d, 1H, J=2.4 Hz), 7.27 (dd, 1H, J=2.4 and8.1 Hz), 7.21 (dd, 1H, J=2.4 and 8.7 Hz), 7.13 (d, 1H, J=1.8 Hz), 6.95(d, 1H, J=8.1 Hz), 6.76 (d, 1H, J=8.7 Hz), 4.28 (s, 2H), 4.20 (s, 4H),2.65 (d, 3H, J=4.8 Hz), 2.15 (s, 3H); LCMS: purity: 97%; MS (m/e): 440(MH⁺).

7.3.8215-Fluoro-N4-(3-hydroxy-4-methylphenyl)-N2-[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926759)

In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(2-hydroxy-4-methylphenyl)-4-pyrimidineamine and4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toproduce5-fluoro-N4-(3-hydroxy-4-methylphenyl)-N2-[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ 10.09 (bs, 1H),9.96 (bs, 1H), 9.44 (bs, 1H), 8.16 (d, 1H, J=4.8 Hz), 7.81 (d, 1H, J=4.8Hz), 7.13-6.94 (m, 6H), 4.29 (s, 2H), 2.64 (d, 3H, J=4.5 Hz), 2.17 (s,3H), 2.07 (s, 3H); LCMS: purity: 99%; MS (m/e): 412 (MH⁺).

7.3.822 5-Fluoro-N2,N4-bis[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine (R926760)

In a like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toprovide5-fluoro-N2,N4-bis[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.30 (s, 1H), 9.02 (s, 1H), 8.06 (d, 1H, J=3.6 Hz),7.94 (d, 1H, J=4.5 Hz), 7.80 (d, 1H, J=4.2 Hz), 7.58 (bs, 1H), 7.31-7.22(m, 3H), 7.05 (d, 1H, J=9.0 Hz), 6.97 (d, 1H, J=7.5 Hz), 4.41 (s, 2H),4.27 (s, 2H), 2.66 (d, 3H, J=4.2 Hz), 2.63 (d, 3H, J=4.2 Hz), 2.18 (s,3H), 2.14 (s, 3H); LCMS: purity: 100%; MS (m/e): 483 (MH⁺).

7.3.8235-Fluoro-N4-(3-hydroxyphenyl)-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine(R926761)

In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3,4,5-trimethoxyaniline were reacted to produce5-fluoro-N4-(3-hydroxyphenyl)-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.33 (s, 1H), 9.17 (s, 1H), 8.99 (s, 1H), 8.06 (d,1H, J=3.3 Hz), 7.27 (d, 1H, J=7.5 Hz), 7.08-7.02 (m, 4H), 6.46 (dd, 1H,J=1.8 and 7.8 Hz), 3.60 (s, 6H), 3.57 (s, 3H); LCMS: purity: 99%; MS(m/e): 387 (MH⁺).

7.3.824N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine(R926762)

In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3,4,5-trimethoxyaniline were reacted to produceN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine¹H NMR (DMSO-d₆): δ 8.08 (d, 1H, J=4.8 Hz), 7.29 (d, 1H, J=2.4 Hz), 7.15(dd, 1H, J=3.0 and 9.0 Hz), 6.91 (s, 1H), 6.76 (d, 1H, J=8.7 Hz), 4.20(s, 4H), 3.61 (s, 6H), 3.59 (s, 3H); LCMS: purity: 97%; MS (m/e): 429(MH⁺).

7.3.825N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3,5-dichloro-4-hydroxyphenyl)-2,4-pyrimidinediamine(R926763)

In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3,5-dichloro-4-hydroxyaniline were reacted to produceN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3,5-dichloro-4-hydroxyphenyl)-2,4-pyrimidinediamine.1H NMR (DMSO-d₆): δ 9.50 (bs, 1H), 9.26 (bd, 2H, J=7.5 Hz), 8.06 (d, 1H,J=3.9 Hz), 7.65 (s, 2H), 7.18-7.13 (m, 2H), 6.80 (d, 1H, J=9.0 Hz), 4.20(s, 4H); LCMS: purity: 100%; MS (m/e): 424 (MH⁺).

7.3.8265-Fluoro-N2-(3,5-dichloro-4-hydroxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926890)

In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3,5-dichloro-4-hydroxyaniline were reacted to produce5-Fluoro-N2-(3,5-dichloro-4-hydroxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.47 (bs, 1H), 9.35 (bs, 1H), 9.22 (bs, 2H), 8.09(d, 1H, J=3.6 Hz), 7.70 (s, 2H), 7.31 (dd, 1H, J=1.2 and 9.3 Hz), 7.10(t, 1H, J=7.5 Hz), 7.00 (bs, 1H), 6.48 (dd, 1H, J=1.2 and 6.9 Hz); LCMS:purity: 93%; MS (m/e): 382 (MH⁺).

7.3.827N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926891)

In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted to produceN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.85 (bs, 1H), 9.70 (bs, 1H), 8.17 (d, 1H, J=4.8Hz), 7.98 (d, 1H, J=3.9 Hz), 7.79 (d, 1H, J=2.4 Hz), 7.65 (dd, 1H, J=3.0and 9.3 Hz), 7.24-7.09 (m, 4H), 6.57 (d, 1H, J=5.7 Hz), 4.34 (s, 2H),3.82 (s, 3H), 2.62 (d, 3H, J=4.8 Hz); LCMS: purity: 95%; MS (m/e): 433(MH⁺).

7.3.8285-Fluoro-N4-(3-fluoro-4-methoxyphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926892)

In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-fluoro-4-methoxyphenyl)-4-pyrimidineamine and3-[(N-methylamino)carbonylmethylene oxy]aniline were reacted to produce5-fluoro-N4-(3-fluoro-4-methoxyphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.68 (bs, 1H), 9.53 (bs, 1H), 8.13 (d, 1H, J=4.2Hz), 7.97 (d, 1H, J=4.8 Hz), 7.76 (dd, 1H, J=2.4 and 13.5 Hz), 7.47 (d,1H, J=7.5 Hz), 7.27-7.08 (m, 4H), 6.54 (d, 1H, J=8.4 Hz), 4.35 (s, 2H),3.80 (s, 3H), 2.63 (d, 3H, J=4.8 Hz); LCMS: purity: 94%; MS (m/e): 416(MH⁺).

7.3.829N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-(3-hydroxy-5-methylphenyl)-2,4-pyrimidinediamine(R926893)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,4-amino-m-cresol hydrogenchloride salt, and diisopropylethylamine werereacted to provideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-(3-hydroxy-5-methylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.06 (s, 1H), 8.94 (s, 1H), 8.11 (s, 1H), 7.86 (d,1H, J=3.9 Hz), 7.21-7.15 (m, 2H), 7.03 (d, 1H, J=8.1 Hz), 6.59 (bd, 2H,J=8.7 Hz), 6.52 (dd, 1H, J=3.0 and 8.1 Hz), 4.17 (s, 4H), 2.05 (s, 3H);LCMS: purity: 99%; MS (m/e): 369 (MH⁺).

7.3.830N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-fluoro-5-trifluoromethylphenyl)-2,4-pyrimidinediamine(R926894)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3-amino-5-fluorobenzotrifluoride were reacted to provideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-fluoro-5-trifluoromethylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.75 (s, 1H), 9.32 (d, 1H, J=1.2 Hz), 8.13 (d, 1H,J=3.6 Hz), 7.99 (d, 1H, J=12.3 Hz), 7.77 (s, 1H), 7.21 (d, 1H, J=2.4Hz), 7.13 (dd, 1H, J=2.1 and 8.7 Hz), 7.03 (d, 1H, J=9.0 Hz), 6.80 (d,1H, J=8.7 Hz), 4.21 (s, 4H); LCMS: purity: 97%; MS (m/e): 425 (MH⁺).

7.3.831N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-methyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine(R926895)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3-amino-5-methylbenzotrifluoride were reacted to provideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-methyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.57 (bs, 1H), 9.39 (bs, 1H), 8.12 (d, 1H, J=3.6Hz), 7.77 (s, 2H), 7.25-7.13 (m, 2H), 7.02 (s, 1H), 6.79 (d, 1H, J=9.0Hz), 4.20 (s, 4H), 2.27 (s, 3H); LCMS: purity: 100%; MS (m/e): 421(MH⁺).

7.3.832N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(5-methoxy-2-methylphenyl)-2,4-pyrimidinediamine(R926896)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and5-methoxy-2-methylaniline were reacted to provideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(5-methoxy-2-methylphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.91 (bs, 1H), 7.61 (d, 1H, J=2.1 Hz), 7.17 (d, 1H,J=3.0 Hz), 7.05 (d, 1H, J=9.3 Hz), 7.03 (dd, 1H, J=3.0 and 8.7 Hz), 6.82(d, 1H, J=8.1 Hz), 6.68-6.60 (m, 2H), 6.55 (dd, 1H, J=2.1 and 8.1 Hz),4.26 (s, 4H), 3.70 (s, 3H), 2.22 (s, 3H); ¹⁹F NMR (282 MHz, CDCl₃):−47450; LCMS: purity: 99%; MS (m/e): 383 (MH⁺).

7.3.833N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-fluoro-5-methylphenyl)-2,4-pyrimidinediamine(R926897)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and2-fluoro-5-methylaniline were reacted to provideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-fluoro-5-methylphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.11 (dd, 1H, J=1.8 and 8.1 Hz), 7.94 (d, 1H, J=2.7Hz), 7.08-6.84 (m, 4H), 6.74-6.67 (m, 1H), 6.64-6.59 (m, 1H), 4.27 (s,4H), 2.28 (s, 3H); ¹⁹F NMR (282 MHz, CDCl₃): −38659, −47267; LCMS:purity: 100%; MS (m/e): 371 (MH⁺).

7.3.834N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3,5-difluorophenyl)-2,4-pyrimidinediamine(R926898)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3,5-difluoroaniline were reacted to provideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3,5-difluorophenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.94 (d, 1H, J=3.3 Hz), 7.20-7.11 (m, 3H), 7.02 (s,1H), 6.92-6.90 (m, 2H), 6.65 (s, 1H), 6.39 (tt, 1H, J=2.4 and 9.0 Hz),4.31 (s, 4H); ¹⁹F NMR (282 MHz, CDCl₃): −31142, −47002; LCMS: purity:97%; MS (m/e): 375 (MH⁺).

7.3.835N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(4-trifluoromethylthiophenyl)-2,4-pyrimidinediamine(R926899)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-(trifluoromethylthio)aniline were reacted to provideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-trifluoromethylthiophenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.73 (s, 1H), 9.47 (s, 1H), 8.13 (d, 1H, J=3.6 Hz),7.79 (d, 2H, J=9.0 Hz), 7.51 (d, 2H, J=9.0 Hz), 7.28 (d, 1H, J=2.1 Hz),7.12 (dd, 1H, J=2.4 and 9.0 Hz), 6.83 (d, 1H, J=8.7 Hz), 4.23 (s, 4H);¹⁹F NMR (282 MHz DMSO-d₆): −12306; LCMS: purity: 97%; MS (m/e): 439(MH⁺).

7.3.836N4-[3-(Benzothiazol-2-yl)-4-chlorophenyl]-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl)-2,4-pyrimidinediamine(R926900)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,N4-[3-(Benzothiazol-2-yl)-4-chlorophenyl)-2-chloro-5-fluoro-4-pyrimidineamineand 3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toprovideN4-[3-(benzothiazol-2-yl)-4-chlorophenyl)-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.77 (s, 1H), 9.30 (s, 1H), 8.49 (d, 1H, J=3.0 Hz),8.25 (dd, 1H, J=3.0 and 9.0), 8.21-8.16 (m, 2H), 8.06 (d, 1H, J=7.8 Hz),7.92 (d, 1H, J=4.8 Hz), 7.63-7.48 (m, 3H), 7.30 (t, 1H, J=1.8 Hz), 7.22(dd, 1H, J=1.8 and 7.5 Hz), 6.95 (t, 1H, J=8.1 Hz), 6.32 (dd, 1H, J=1.2and 8.1 Hz), 4.29 (s, 2H), 2.62 (d, 1H, J=4.8 Hz); LCMS: purity: 100%;MS (m/e): 536 (MH⁺).

7.3.8375-Fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(3-methoxy-4-methylphenyl)-2,4-pyrimidinediamine(R926902)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-Chloro-5-fluoro-N4-(3-methoxy-4-methylphenyl)-4-pyrimidineamine and3-methoxy-4-methylaniline were reacted to provide5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(3-methoxy-4-methylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.78 (bs, 1H), 9.63 (bs, 1H), 8.15 (d, 1H, J=4.5Hz), 7.94 (d, 1H, J=4.5 Hz), 7.94 (d, 1H, J=4.5 Hz), 7.30 (dd, 1H, J=1.8and 8.4 Hz), 7.25-7.04 (m, 5H), 6.57 (d, 1H, J=8.1 Hz), 4.31 (s, 2H),3.66 (s, 3H), 2.62 (d, 1H, J=4.8 Hz), 2.09 (s, 3H); LCMS: purity: 95%;MS (m/e): 412 (MH⁺).

7.3.8385-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(methoxycarbonyl)-(1H)-indol-6-yl])-2,4-pyrimidinediamine(R926903)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and6-amino-2-(methoxycarbonyl)-(1H)-indole were reacted to provide5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(methoxycarbonyl)-(1H)-indol-6-yl])-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 11.53 (s, 1H), 9.37 (s, 1H), 9.18 (d, 2H, J=9.9 Hz),8.08 (d, 1H, J=3.6 Hz), 7.96 (bs, 1H), 7.46 (d, 1H, J=9.0 Hz), 7.39-7.35(m, 2H), 7.16 (t, 1H, J=2.4 Hz), 7.10-7.04 (m, 2H), 6.48 (dd, 1H, J=2.4and 7.5 Hz), 3.82 (s, 3H); LCMS: purity: 95%; MS (m/e): 394 (MH⁺).

7.3.8395-Fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-[2-(methoxycarbonyl)-(1H)-indol-6-yl]-2,4-pyrimidinediamine(R926904)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoroN4-[2-(methoxycarbonyl)-(1H)-indol-6-yl])-4-pyrimidineamine and3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted to provide5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-[2-(methoxycarbonyl)-(1H)-indol-6-yl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 9.05 (bs, 1H), 8.35 (s, 1H), 8.00 (bs, 1H), 7.66-7.62(m, 2H), 7.27-7.17 (m, 3H), 7.01-6.90 (m, 3H), 6.64 (dd, 1H, J=2.4 and8.1 Hz), 6.40 (bs, 1H). 4.49 (s, 2H), 3.94 (s, 3H), 2.75 (d, 3H, J=5.1Hz); LCMS: purity: 86%; MS (m/e): 465 (MH⁺).

7.3.840N4-[3-[[4-(Ethoxycarbonyl)piperidino]methyl]phenyl]-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl-2,4-pyrimidinediamine(R926905)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[3-[[4-(ethoxycarbonyl)piperidino]methyl]phenyl]-4-pyrimidineamineand 3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toprovide5-fluoro-N4-[3-[[4-(ethoxycarbonyl)piperidino]methyl]phenyl]-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): 9.33 (s, 1H), 9.20 (s, 1H), 8.09 (d, 1H, J=4.2 Hz),7.93 (d, 1H, J=4.8 Hz), 7.82 (d, 1H, J=8.1 Hz), 7.55 (s, 1H), 7.35 (t,1H, J=2.4 Hz), 7.29-7.22 (m, 2H), 7.09 (t, 1H, J=8.1 Hz), 6.96 (d, 1H,J=7.8 Hz), 6.47 (dd, 1H, J=2.4 and 8.1 Hz), 4.32 (s, 2H), 4.02 (q, 2H,J=6.9 Hz), 3.39 (s, 2H), 2.73 (bd, 2H, J=11.1 Hz), 2.63 (d, 3H, J=4.5Hz), 2.30-2.20 (m, 1H), 1.94 (t, 2H, J=11.1 Hz), 1.74 (d, 2H, J=9.9 Hz),1.60-1.50 (m, 2H), 1.14 (t, 3H, J=6.9 Hz); LCMS: purity: 99%; MS (m/e):537 (M-CH₂+).

7.3.841N2-[3-(Ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926906)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-(ethoxycarbonyl-1,1-dimethylmethyleneoxy)aniline were reacted toprovideN2-[3-(ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.91 (d, 1H, J=4.8 Hz), 7.20-7.03 (m, 6H), 6.67 (td,1H, J=2.1 and 7.5 Hz), 6.57-6.53 (m, 1H), 4.19 (q, 2H, J=6.9 Hz), 1.53(s, 6H), 1.20 (t, 3H, J=6.9 Hz); ¹⁹F NMR (282 MHz, CD₃OD): −46120; LCMS:purity: 91%; MS (m/e): 427 (MH⁺).

7.3.842N2-[3-(Ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926907)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3-(ethoxycarbonyl-1,1-dimethylmethyleneoxy)aniline were reacted toprovideN2-[3-(ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.92 (d, 1H, J=3.0 Hz), 7.21-7.08 (m, 4H), 7.00 (dd,1H, J=2.4 and 8.4 Hz), 6.93 (bs, 1H), 6.86 (d, 1H, J=8.7 Hz), 6.99 (d,1H, J=2.4 Hz), 6.45 (ddd, 1H, J=1.2, 1.2, and 7.8 Hz), 4.27 (s, 4H),4.23 (q, 2H, J=6.9 Hz), 1.60 (s, 6H), 1.23 (t, 3H, J=6.9 Hz); ¹⁹F NMR(282 MHz, CDCl₃): −47216; LCMS: purity: 85%; MS (m/e): 469 (MH⁺).

7.3.843N2-[3-(Ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxy-4-methylphenyl)-2,4-pyrimidinediamine(R926908)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(2-hydroxy-4-methylphenyl)-4-pyrimidineamine and3-(ethoxycarbonyl-1,1-dimethylmethyleneoxy)aniline were reacted toprovideN2-[3-(ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxy-4-methylphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.86 (bs, 1H), 7.80 (bs, 1H), 7.53 (s, 1H), 7.16-6.86(m, 4H), 6.54 (d, 2H, J=7.5 Hz), 4.21 (q, 2H, J=6.9 Hz), 3.48 (s, 2H),2.20 (s, 3H), 1.60 (s, 6H), 1.22 (t, 3H, J=6.9 Hz); ¹⁹F NMR (282 MHz,CDCl₃): −46808; LCMS: purity: 96%; MS (m/e): 441 (MH⁺).

7.3.844N2-[3-(Ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-5-fluoro-N4-[(1H)-indol-6-yl]-2,4-pyrimidinediamine(R926909)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[(1H)indol-6-yl]-4-pyrimidineamine and3-(ethoxycarbonyl-1,1-dimethylmethyleneoxy)aniline were reacted toprovideN2-[3-(Ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-5-fluoro-N4-[(1H)-indol-6-yl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 9.43 (bs, 1H), 8.64 (s, 1H), 7.92 (d, 1H, J=3.6 Hz),7.66 (t, 1H, J=2.4 Hz), 7.54 (d, 1H, J=8.4 Hz), 7.44 (s, 1H), 7.19 (t,1H, J=3.0 Hz), 7.15 (d, 1H, J=8.1 Hz), 6.96 (d, 1H, J=3.0 Hz), 6.80 (dd,1H, J=1.8 and 7.5 Hz), 6.77 (dd, 1H, J=1.8 and 8.1 Hz), 6.52 (dd, 1H,J=1.8 and 7.5 Hz), 6.49-6.46 (m, 1H), 4.32 (q, 2H, J=7.2 Hz), 1.57 (s,6H), 1.31 (t, 3H, J=7.2 Hz); ¹⁹F NMR (282 MHz, CDCl₃): −47190; LCMS:purity: 93%; MS (m/e): 450 (MH⁺).

7.3.8455-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)carbonyl-1,1-dimethylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926913)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-(N-methylamino)carbonyl-1,1-dimethylmethyleneoxy)aniline were reactedto provide5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)carbonyl-1,1-dimethylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.1H NMR (DMSO-d₆): δ 9.35 (s, 1H), 9.20 (s, 1H), 9.17 (s, 1H), 8.07 (d,1H, J=3.3 Hz), 7.93 (d, 1H, J=3.9 Hz), 7.40-7.29 (m, 3H), 7.13-7.02 (m,3H), 6.47 (d, 1H, J=7.5 Hz), 6.33 (d, 1H, J=7.5 Hz), 2.60 (s, 3H), 1.37(s, 6H); LCMS: purity: 97%; MS (m/e): 412 (MH⁺).

7.3.8465-Fluoro-N4-(1,2,3,4-tetrahydroisoquin-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926914)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-4-pyrimidineamineand 3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toprovide5-fluoro-N4-(1,2,3,4-tetrahydroisoquin-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 7.90 (d, 1H, J=3.3 Hz), 7.47 (d, 1H, J=2.4 Hz),7.42-7.37 (m, 2H), 7.16 (t, 1H, J=8.4 Hz), 7.10-7.04 (m, 2H), 6.50 (ddd,1H, J=1.2, 2.4, and 8.1 Hz), 4.26 (s, 2H), 3.93 (s, 2H), 3.12 (t, 2H,J=6.3 Hz), 2.84-2.76 (m, 5H); ¹⁹F NMR (282 MHz, CD₃OD): −47489; LCMS:purity: 87%; MS (m/e): 423 (MH⁺).

7.3.847N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[(N-methylamino)carbonyl-1,1-dimethylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926915)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3-(N-methylamino)carbonyl-1,1-dimethylmethyleneoxy)aniline were reactedto provideN4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[(N-methylamino)carbonyl-1,1-dimethylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.26 (t, 1H, J=7.5 Hz), 7.19 (d, 1H, J=9.3 Hz), 7.13(d, 1H, J=2.4 Hz), 7.06 (dd, 1H, J=2.4 and 8.7 Hz), 7.04-7.03 (m, 1H),6.83 (d, 1H, J=9.0 Hz), 6.75 (d, 1H, J=7.2 Hz), 4.25 (s, 4H), 2.76 (s,3H), 1.43 (s, 6H); LCMS: purity: 97%; MS (m/e): 454 (MH⁺).

7.3.8485-Fluoro-N4-[3-[(N-allylamino)carbonyloxy]phenyl]-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926917)

A mixture of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (20 mg, 0.052 mmol), allylisocyanate (13 mg, 0.16 mmol), and 2-(N,N-dimethylamino)pyridine (18 mg,0.15 mmol) in anhydrous THF (1 mL) were heated at 60° C. in a sealedvial for 2 days. The reaction was diluted with ethyl acetate and washedwith 1N HCl and brine. Concentration gave an oily residue which waspurified by preparative TLC (5% methanol/dichloromethane) to give theproduct5-fluoro-N4-[3-[(N-allylamino)carbonyloxy]phenyl]-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine. ¹H NMR (CD₃OD): δ 7.93 (d, 1H, J=3.6Hz), 7.62-7.55 (m, 2H), 7.32 (s, 1H), 7.30 (t, 1H, J=8.1 Hz), 7.19-7.15(m, 2H), 6.82 (dd, 1H, J=2.4 and 8.1 Hz), 6.61 (m, 1H), 5.96-5.82 (m,1H), 5.24 (dd, 1H, J=1.8 and 16.8 Hz), 5.13 (dd, 1H, J=1.8 and 11.7 Hz),4.41 (s, 2H), 3.79 (d, 1H, J=5.4 Hz), 2.80 (s, 3H); ¹⁹F NMR (282 MHz,CD₃OD): −47357; LCMS: purity: 99%; MS (m/e): 468 (MH⁺).

7.3.8495-Fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-[3-[[(N-isopropylamino)carbonyl]-N-isopropylamino)carbonyloxy]phenyl]-2,4-pyrimidinediamine (R926916)

In a like manner to the preparation of5-fluoro-N4-[3-[(N-allylamino)carbonyloxy]phenyl]-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamineand isopropyl isocyanate were reacted to provide5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-[3-[[(N-isopropylamino)carbonyl]-N-isopropylamino)carbonyloxy]phenyl]-2,4-pyrimidinediamine.1H NMR (DMSO-d₆): δ 9.40 (bs, 1H), 9.27 (bs, 1H), 8.12 (d, 1H, J=3.6Hz), 7.94 (d, 1H, J=3.9 Hz), 7.78 (d, 1H, J=8.7 Hz), 7.64 (d, 1H, J=7.5Hz), 7.46 (s, 1H), 7.36-7.26 (m, 3H), 7.12 (t, 1H, J=8.1 Hz), 6.81-6.74(m, 1H), 6.47 (dd, 1H, J=2.4 and 8.1 Hz), 5.43 (d, 1H, J=3.9 Hz), 4.36(s, 2H), 3.65-3.55 (m, 2H), 3.14 (s, 2H), 2.63 (d, 3H, J=3.9 Hz), 1.10(d, 6H, J=7.2 Hz), 0.97 (d, 6H, J=6.6 Hz).

7.3.850N4-[3-[[N-(Ethoxycarbonylmethyl)amino]carbonyloxy]phenyl]-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926918)

In a like manner to the preparation of5-fluoro-N4-[3-[(N-allylamino)carbonyloxy]phenyl]-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamineand ethyl isocyanatoacetate were reacted to provideN4-[3-[[N-(ethoxycarbonylmethyl)amino]carbonyloxy]phenyl]-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.94 (d, 1H, J=3.3 Hz), 7.69 (t, 1H, J=1.8 Hz), 7.56(ddd, 1H, J=1.2, 1.2, and 8.1 Hz), 7.35 (m, 1H), 7.31 (t, 1H, J=8.1 Hz),7.18 (d, 1H, J=2.4 Hz), 7.17 (d, 1H, J=1.2 Hz), 6.84 (dd, 1H, J=2.4 and8.1 Hz), 6.63-6.58 (m, 1H), 4.42 (s, 2H), 4.20 (q, 2H, J=7.2 Hz), 3.93(s, 2H), 2.80 (s, 3H), 1.27 (t, 3H, J=7.2 Hz); ¹⁹F NMR (282 MHz, CD₃OD):−47371; LCMS: purity: 89%; MS (m/e): 513 (MH⁺).

7.3.851N4-[3-[(N-(Ethylamino)carbonyloxy]phenyl]-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926919)

In a like manner to the preparation of5-fluoro-N4-[3-[(N-allylamino)carbonyloxy]phenyl]-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamineand ethyl isocyanate were reacted to provideN4-[3-[(N-(ethylamino)carbonyloxy]phenyl]-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.94 (d, 1H, J=3.3 Hz), 6.84-6.79 (m, 2H), 7.61-7.55(m, 2H), 6.62-6.56 (m, 2H), 7.33-7.27 (m, 1H), 7.19-7.17 (m, 1H), 4.41(s, 2H), 3.23 (q, 2H, J=7.2 Hz), 2.80 (s, 3H), 1.17 (t, 3H, J=7.2 Hz);¹⁹F NMR (282 MHz, CD₃OD): −47378; LCMS: purity: 100%; MS (m/e): 455(MH⁺).

7.3.8525-Fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(4-methyl-3-trifluoromethylphenyl)-2,4-pyrimidinediamine(R926922)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(4-methyl-3-trifluoromethylphenyl)-4-pyrimidineamineand 3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toprovide5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(4-methyl-3-trifluoromethylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.79 (bs, 1H), 9.48 (bs, 1H), 8.17 (d, 1H, J=4.2Hz), 8.10 (d, 1H, J=6.3 Hz), 7.96 (d, 1H, J=4.8 Hz), 7.89 (d, 1H, J=2.1Hz), 7.38 (d, 1H, J=9.0 Hz), 7.26-7.20 (m, 2H), 7.11 (t, 1H, J=8.4 Hz),6.53 (d, 1H, J=8.4 Hz), 4.33 (s, 2H), 2.62 (d, 3H, J=4.8 Hz), 2.39 (s,3H); LCMS: purity: 94%; MS (m/e): 450 (MH⁺).

7.3.8535-Fluoro-N4-(4-fluoro-3-methylphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926923)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(4-fluoro-3-methylphenyl)-4-pyrimidineamine and3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted to provide5-Fluoro-N4-(4-fluoro-3-methylphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.67 (bs, 1H), 9.51 (bs, 1H), 8.14 (d, 1H, J=4.8Hz), 7.95 (d, 1H, J=4.2 Hz), 7.64 (dd, 1H, J=2.7 and 6.9 Hz), 7.57-7.50(m, 1H), 7.23-7.06 (m, 4H), 6.55 (d, 1H, J=7.5 Hz), 4.33 (s, 2H), 2.63(d, 3H, J=4.8 Hz), 2.19 (s, 3H); LCMS: purity: 94%; MS (m/e): 400 (MH⁺).

7.3.8545-Fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(3-trifluoromethylthiophenyl)-2,4-pyrimidinediamine(R926925)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-trifluoromethylthiophenyl)-4-pyrimidineamine and3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted to provide5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(3-trifluoromethylthiophenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.83 (bs, 1H), 9.49 (bs, 1H), 8.21-8.15 (m, 2H),8.01 (s, 1H), 7.94 (bs, 1H), 7.49 (t, 1H, J=7.8 Hz), 7.38 (d, 1H, J=7.8Hz), 7.29 (s, 1H), 7.22 (d, 1H, J=7.5 Hz), 7.14 (t, 1H, J=8.4 Hz), 6.54(d, 1H, J=9.9 Hz), 4.34 (s, 2H), 2.62 (d, 3H, J=4.8 Hz); LCMS: purity:98%; MS (m/e): 468 (MH⁺).

7.3.855N2-[3,5-Bis(methoxycarbonylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926926)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3,5-bis(methoxycarbonylmethyleneoxy)aniline were reacted to provideN2-[3,5-bis(methoxycarbonylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.92 (d, 1H, J=4.2 Hz), 7.20-7.10 (m, 3H), 6.92 (d,2H, J=2.4 Hz), 6.52 (ddd, 1H, J=1.8, 1.8, and 7.5 Hz), 6.12 (t, 1H,J=2.4 Hz), 4.55 (s, 4H), 3.77 (s, 6H); ¹⁹F NMR (282 MHz, CD₃OD): −47342;LCMS: purity: 92%; MS (m/e): 473 (MH⁺).

7.3.8565-Fluoro-N2-[3-hydroxy-5-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926927)

In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-hydroxy-5-(methoxycarbonylmethyleneoxy)aniline were reacted to produce5-fluoro-N2-[3-hydroxy-5-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 8.13 (d, 1H, J=4.8 Hz), 7.37-7.33 (m, 1H), 7.11 (t,1H, J=8.4 Hz), 7.07-7.05 (m, 1H), 6.73-6.65 (m, 2H), 6.51 (dd, 1H, J=2.1and 8.1 Hz), 5.97 ((s, 1H), 4.59 (s, 2H), 3.67 (s, 3H); LCMS: purity:93%; MS (m/e): 401 (MH⁺).

7.3.857N2-[3-[(N-Ethylamino)carbonyloxy]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926928)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-[(N-ethylamino)carbonyloxy]aniline were reacted to provideN2-[3-[(N-ethylamino)carbonyloxy]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.92 (d, 1H, J=3.0 Hz), 7.67-7.55 (m, 2H), 7.24 (t,1H, J=7.5 Hz), 7.16 (t, 1H, J=7.5 Hz), 7.07-6.98 (m, 2H), 6.84-6.79 (m,2H), 6.67 (m, 2H), 6.60 (d, 1H, J=7.5 Hz), 5.22-5.14 (m, 1H), 3.36-3.27(m, 2H), 2.95 (s, 1H), 2.88 (s, 1H), 1.20 (t, 3H, J=7.5 Hz); ¹⁹F NMR(282 MHz, CDCl₃): −47012; LCMS: purity: 99%; MS (m/e): 384 (MH⁺).

7.3.858 5-Fluoro-N2-[3-hydroxy-5-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926929)

A solution of5-fluoro-N2-[3-hydroxy-5-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(56 mg, 0.13 mmol), methylamine hydrochloride (90 mg, 1.3 mmol), anddiisopropylethylamine (0.12 mL, 0.70 mmol) in methanol (2 mL) was heatedat 100° C. for 8 h. The cooled reaction mixture was poured into 1N HCl(20 mL) saturated with NaCl, and extracted with ethyl acetate.Purification by preparative TLC (5% methanol/dichloromethane) gave theproduct,5-fluoro-N2-[3-hydroxy-5-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.1H NMR (DMSO-d₆): δ 9.29 (bs, 1H), 9.16 (s, 1H), 9.01 (s, 1H), 8.06 (d,1H, J=3.3 Hz), 7.87 (d, 1H, J=4.8 Hz), 7.42 (dd, 1H, J=1.5 and 8.1 Hz),7.13-7.05 (m, 2H), 6.89-6.81 (m, 2H), 6.45 (dd, 1H, J=2.4 and 8.4 Hz),5.92 (t, 1H, J=2.4 Hz), 4.28 (s, 2H), 3.30 (bs, 1H), 2.63 (s, 3H); LCMS:purity: 94%; MS (m/e): 400 (MH⁺).

7.3.859N2-[3,5-Bis[(N-methylamino)carbonylmethyleneoxy]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926930)

In a like manner to the preparation of5-fluoro-N2-[3-hydroxy-5-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N2-[3,5-bis(methoxycarbonylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine,methylamine hydrochloride, and diisopropylethylamine were reacted togiveN2-[3,5-Bis[(N-methylamino)carbonylmethyleneoxy]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.91 (bs, 1H), 7.25 (t, 1H, J=1.8 Hz), 7.14-7.11 (m,1H), 6.98 (s, 1H), 6.97 (s, 1H), 6.55-6.50 (m, 1H), 6.26-6.23 (m, 1H),4.39 (s, 4H), 2.81 (s, 6H); ¹⁹F NMR (282 MHz, CD₃OD): −47307; LCMS:purity: 99%; MS (m/e): 471=(MH⁺).

7.3.860 5-Fluoro-N4-[(1H)-indol-5-yl]-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine (R926931)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[(1H)-indol-5-yl]-4-pyrimidineamine and3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted to provide5-fluoro-N4-[(1H)-indol-5-yl]-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 11.09 (bs, 1H), 9.93 (bs, 1H), 9.67 (bs, 1H), 8.12(d, 1H, J=4.81 Hz), 7.94-7.82 (m, 2H), 7.37-7.22 (m, 4H), 7.13 (bs, 1H),7.07 (t, 1H, J=8.1 Hz), 6.58 (d, 1H, J=7.8 Hz), 6.37 (s, 1H), 4.32 (s,2H), 2.61 (d, 3H, J=4.2 Hz); LCMS: purity: 92%; MS (m/e): 407 (MH⁺).

7.3.8615-Fluoro-N2-(3-hydroxyphenyl)-N4-[(1H)-indol-5-yl]-2,4-pyrimidinediamine(R926932)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[(1H)-indol-5-yl]-4-pyrimidineamine and3-hydroxyaniline were reacted to provide5-fluoro-N2-(3-hydroxyphenyl)-N4-[(1H)-indol-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 11.13 (s, 1H), 10.25 (bs, 1H), 9.87 (bs, 1H), 9.43(bs, 1H), 8.16 (d, 1H, J=5.1 Hz), 7.89 (d, 1H, J=0.09 Hz), 7.39-7.27 (m,3H), 7.03-6.94 (m, 2H), 6.83 (s, 1H), 6.48 (d, 1H, J=7.5 Hz), 6.40 (t,1H, J=2.1 Hz); LCMS: purity: 92%; MS (m/e): 336 (MH⁺).

7.3.8625-Fluoro-N4-[(1H)-indol-6-yl]-N2-[3-[(N-methylamino)carbonyl]phenyl]-2,4-pyrimidinediamine(R926933)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[(1H)indol-6-yl]-4-pyrimidineamine and3-[(N-methylamino)carbonyl]aniline were reacted to provide5-fluoro-N4-[(1H)indol-6-yl]-N2-[3-[(N-methylamino)carbonyl]phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.99 (t, 1H, J=1.8 Hz), 7.89 (d, 1H, J=3.6 Hz),7.78-7.76 (m, 1H), 7.70 (ddd, 1H, J=1.2, 2.4, and 8.4 Hz), 7.50 (d, 1H,J=9.0 Hz), 7.31 (td, 1H, J=1.2 and 7.5 Hz), 7.23-7.17 (m, 3H), 6.43 (dd,1H, J=1.2 and 3.6 Hz), 2.73 (s, 3H); ¹⁹F NMR (282 MHz, CD₃OD): −47513;LCMS: purity: 99%; MS (m/e): 377 (MH⁺).

7.3.8635-Fluoro-N4-[(1H)-indol-6-yl]-N2-[3-(N-morpholinocarbonyl)phenyl]-2,4-pyrimidinediamine(R926934)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[(1H)indol-6-yl]-4-pyrimidineamine and3-(N-morpholinocarbonyl)aniline were reacted to provide5-fluoro-N4-[(1H)-indol-6-yl]-N2-[3-(N-morpholinocarbonyl)phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.96 (d, 1H, J=4.8 Hz), 7.73 (t, 1H, J=2.4 Hz), 7.66(d, 1H, J=1.2 Hz), 7.52 (d, 1H, J=8.1 Hz), 7.49 (ddd, 1H, J=0.09, 2.1,and 8.1 Hz), 7.33-7.26 (m, 2H), 7.19 (dd, 1H, J=1.8 and 8.7 Hz),7.12-7.06 (m, 1H), 6.45 (dd, 1H, J=1.3 and 3.0 Hz), 3.62-3.15 (m, 8H);¹⁹F NMR (282 MHz, CD₃OD): −46545; LCMS: purity: 91%; MS (m/e): 433(MH⁺).

7.3.864N2-[3-[[4-(Ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N4-[(1H)-indol-6-yl]-2,4-pyrimidinediamine(R926935)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[(1H)indol-6-yl]-4-pyrimidineamine and3-[4-(ethoxycarbonyl)piperidino]aniline were reacted to provideN2-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N4-[(1H)-indol-6-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.99 (d, 1H, J=5.1 Hz), 7.64-7.58 (m, 2H), 7.52 (d,1H, J=8.7 Hz), 7.48 (ddd, 1H, J=1.2, 2.4, and 8.1 Hz), 7.34-7.27 (m,2H), 7.19-7.13 (m, 2H), 6.46 (dd, 1H, J=1.2 and 4.2 Hz), 4.40-4.27 (m,1H), 4.13 (q, 2H, J=6.9 Hz), 3.56-3.41 (m, 1H), 2.95-2.82 (m, 2H),2.58-2.47 (m, 1H), 1.98-1.82 (m, 1H), 1.75-7.60 (m, 1H), 1.58-1.39 (m,2H), 1.24 (t, 3H, J=6.9 Hz); ¹⁹F NMR (282 MHz, CD₃OD): −46101; LCMS:purity: 90%; MS (m/e): 503 (MH⁺).

7.3.8655-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)carbonyl]phenyl]-2,4-pyrimidinediamine(R926936)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-[(N-methylamino)carbonyl]aniline were reacted to provide5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)carbonyl]phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.01 (d, 1H, J=5.4 Hz), 7.84 (t, 1H, J=1.8 Hz),7.68-7.61 (m, 2H), 7.45 (t, 1H, J=8.4 Hz), 7.16-7.03 (m, 3H), 6.68 (td,1H, J=1.2 and 8.7 Hz), 2.90 (s, 3H); LCMS: purity: 95%; MS (m/e): 354(MH⁺).

7.3.8665-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-propylamino)carbonyl]phenyl]-2,4-pyrimidinediamine(R926937)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-[(N-propylamino)carbonyl]aniline were reacted to provide5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-propylamino)carbonyl]phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.00 (d, 1H, J=5.4 Hz), 7.84 (t, 1H, J=1.8 Hz),7.69-7.59 (m, 2H), 7.44 (t, 1H, J=7.5 Hz), 7.16-7.05 (m, 3H), 6.67 (td,1H, J=2.4 and 7.2 Hz), 3.34-3.29 (m, 2H), 1.65-1.56 (m, 2H), 0.96 (t,3H, J=7.5 Hz); ¹⁹F NMR (282 MHz, CD₃OD): −46049; LCMS: purity: 94%; MS(m/e): 382 (MH⁺).

7.3.8675-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-morphonlinocarbonyl)phenyl]-2,4-pyrimidinediamine(R926938)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-(N-morpholinocarbonyl)aniline were reacted to provide5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-morphonlinocarbonyl)phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.93 (d, 1H, J=3.6 Hz), 7.84 (t, 1H, J=1.8 Hz), 7.62(ddd, 1H, J=1.2, 2.4, and 8.1 Hz), 7.32 (t, 1H, J=8.4 Hz), 7.19-7.10 (m,3H), 6.96 (dd, 1H, J=1.2 and 7.8 Hz), 6.56 (ddd, 1H, J=1.2, 3.0, and 6.9Hz), 3.78-3.34 (m, 8H); ¹⁹F NMR (282 MHz, CD₃OD): −47323; LCMS: purity:100%; MS (m/e): 410 (MH⁺).

7.3.868N2-[3-[[4-(Ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926939)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-[[4-(ethoxycarbonyl)piperidino]carbonyl]aniline were reacted toprovideN2-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.92 (d, 1H, J=3.6 Hz), 7.82 (s, 1H), 7.62 (td, 1H,J=1.2 and 8.4 Hz), 7.30 (t, 1H, J=8.4 Hz), 7.19-7.09 (m, 3H), 6.93 (d,1H, J=7.5 Hz), 6.55 (td, 1H, J=1.2 and 7.5 Hz), 4.43 (bd, 1H, J=12.3Hz), 4.13 (q, 2H, J=6.9 Hz), 3.7 (bd, 1H, J=11.7 Hz), 3.10-2.92 (m, 2H),2.67-2.55 (m, 1H), 2.06-1.50 (m, 4H), 1.24 (t, H, J=6.9 Hz); ¹⁹F NMR(282 MHz, CD₃OD): −47299; LCMS: purity: 99%; MS (m/e): 480 (MH⁺).

7.3.869N4-[3-[[4-(Ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926940)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-4-pyrimidineamineand 3-hydroxyaniline were reacted to provideN4-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.93 (d, 1H, J=3.6 Hz), 7.89 (t, 1H, J=1.8 Hz), 7.83(td, 1H, J=1.2 and 8.4 Hz), 7.41 (t, 1H, J=7.8 Hz), 7.11-6.95 (m, 4H),6.41 (td, 1H, J=1.8 and 7.2 Hz), 4.44 (bd, 1H, J=12.9 Hz), 4.10 (q, 2H,J=7.2 Hz), 3.73 (bd, 1H, J=12.3 Hz), 3.18-2.98 (m, 2H), 2.67-2.55 (m,1H), 2.05-1.53 (m, 4H), 1.23 (t, 3H, J=7.2 Hz); ¹⁹F NMR (282 MHz,CD₃OD): −47483; LCMS: purity: 99%; MS (m/e): 480 (MH⁺).

7.3.870N4-[3-[[4-(Ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926941)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-4-pyrimidineamineand 3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toprovideN4-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.95 (d, 1H, J=3.3 Hz), 7.90 (t, 1H, J=1.8 Hz), 7.80(ddd, 1H, J=0.09, 2.1, 8.1 Hz), 7.39 (t, 1H, J=7.5 Hz), 7.31 (t, 1H,J=1.2 Hz), 7.17-7.06 (m, 3H), 6.60-6.54 (m, 1H), 4.48-4.38 (m, 3H), 4.10(q, 2H, J=6.9 Hz), 3.78-3.65 (m, 1H), 3.17-2.95 (m, 2H), 2.79 (s, 3H),2.65-2.53 (m, 1H), 2.01-1.52 (m, 4H), 1.22 (t, 3H, J=6.9 Hz); ¹⁹F NMR(282 MHz, CD₃OD): −47309; LCMS: purity: 99%; MS (m/e): 551 (MH⁺).

7.3.871 Reaction of 3-hydroxyaniline and2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-yl)-4-pyrimidineamine

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-yl)-4-pyrimidineamineand 3-hydroxyaniline were reacted to provide two products, R926942 andR926943.

7.3.872N4-(1-Ethoxy-1,2,3,4-tetrahydronaphthalen-7-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926942)

¹H NMR (DMSO-d₆): δ 9.23 (bs, 1H), 9.14 (bs, 1H), 8.97 (bs, 1H), 8.04(d, 1H, J=3.6 Hz), 7.71 (dd, 1H, J=2.4 and 7.5 Hz), 7.56 (bs, 1H),7.14-6.98 (m, 3H), 6.93 (t, 1H, J=8.1 Hz), 6.29 (bd, 1H, J=7.2 Hz), 4.35(bs, 1H), 3.59-3.36 (m, 2H), 2.69-2.60 (m, 2H), 1.89-1.78 (m, 2H),1.72-1.56 (m, 2H), 1.08 (t, 3H, J=6.9 Hz); LCMS: purity: 96%; MS (m/e):395 (MH⁺).

7.3.8735-Fluoro-N4-(3,4-dihydronaphthalen-7-yl)-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926943)

¹H NMR (DMSO-d₆): δ 9.19 (bs, 2H), 9.01 (s, 1H), 8.04 (d, 1H, J=3.6 Hz),7.56-7.46 (m, 2H), 7.16-7.03 (m, 3H), 6.94 (t, 1H, J=8.1 Hz), 6.46 (d,1H, J=9.6 Hz), 6.03 (dd, 1H, J=1.8 and 8.1 Hz), 6.09-6.01 (m, 1H), 2.69(t, 2H, J=8.4 Hz), 2.28-2.20 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d6):−46541; LCMS: purity: 98%; MS (m/e): 349 (MH⁺).

7.3.8745-Fluoro-N4-(3,4-dihydronaphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926944)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-yl)-4-pyrimidineamineand 3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toprovide5-fluoro-N4-(3,4-dihydronaphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 8.07 (d, 1H, J=3.9 Hz), 7.53-7.45 (m, 2H), 7.32-7.29(m, 2H), 7.11-7.01 (m, 2H), 6.49-6.40 (m, 2H), 6.08-6.00 (m, 1H), 4.32(s, 2H), 2.69 (t, 2H, J=8.4 Hz), 2.62 (s, 3H); LCMS: purity: 99%; MS(m/e): 420 (MH⁺).

7.3.875N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926945)

In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and3-hydroxyaniline were reacted to produceN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.91 (d, 1H, J=5.4 Hz), 7.71 (d, 1H, J=2.4 Hz), 7.58(dd, 1H, J=3.0 and 9.0 Hz), 7.15 (t, 1H, J=8.4 Hz), 7.06 (d, 1H, J=8.7Hz), 6.92 (td, 1H, J=1.8 and 9.9 Hz), 6.88 (t, 1H, J=1.8 Hz), 6.61 (ddd,1H, J=1.2, 2.4, and 8.1 Hz), 3.89 (s, 3H); ¹⁹F NMR (282 MHz, CD₃OD):−46612; LCMS: purity: 98%; MS (m/e): 362 (MH⁺).

7.3.876N2,N4-Bis(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926946)

In a like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-methoxyaniline werereacted to provideN2,N4-Bis(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1HNMR (DMSO-d₆): δ 9.90 (bs, 1H), 9.68 (bs, 1H), 8.16 (d, 1H, J=4.8 Hz),7.72 (d, 1H, J=2.4 Hz), 7.65 (d, 1H, J=2.1 Hz), 7.58 (dd, 1H, J=2.4 and9.0 Hz), 7.38 (dd, 1H, J=2.7 and 9.3 Hz), 7.12 (d, 1H, J=8.7 Hz), 7.12(d, 1H, J=8.7 Hz), 7.05 (d, 1H, J=8.7 Hz), 3.83 (s, 3H), 3.79 (s, 3H);LCMS: purity: 99%; MS (m/e): 410 (MH⁺).

7.3.8775-Fluoro-N4-(1,2,3,4-tetrahydro-1-oxonaphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926947)

In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-oxo-naphthalen-7-yl)-4-pyrimidineamineand 3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toprovide5-fluoro-N4-(1,2,3,4-tetrahydro-1-oxo-naphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ 9.89 (bs, 1H),9.55 (bs, 1H), 8.17 (d, 1H, J=4.2 Hz), 8.04-7.93 (m, 3H), 7.32 (d, 1H,J=8.7 Hz), 7.25-7.16 (m, 2H), 7.09 (t, 1H, J=7.5 Hz), 6.52 (dd, 1H,J=2.4 and 8.1 Hz), 4.28 (s, 2H), 2.90 (t, 2H, J=6.0 Hz), 2.63 (d, 3H,J=4.8 Hz), 2.59 (t, 2H, J=6.6 Hz), 2.02 (t, 2H, J=6.6 Hz); LCMS: purity:93%; MS (m/e): 436 (MH⁺).

7.3.8785-Fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxyiminonaphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926948)

A solution of5-fluoro-N4-(1,2,3,4-tetrahydro-1-oxo-naphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(42 mg, 0.095 mmole) and hydroxylamine hydrochloride (8.5 mg, 0.12mmole) in DMF (1 mL) was heated at 60° C. for 12 h.

The reaction mixture was cooled to rt and then poured into brine (20mL). A brown solid was collected by suction filtration and furtherpurified by reverse phase chromatography to provide5-fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxyiminonaphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 8.13-8.05 (m, 2H), 7.99-7.92 (m, 2H), 7.77-7.72 (m,1H), 7.33-7.21 (m, 2H), 7.14 (d, 1H, J=8.7 Hz), 7.10-7.02 (m, 1H), 6.47(dd, 1H, J=2.4 and 7.5 Hz), 4.30 (s, 2H), 2.90 (t, 1H, J=6.0 Hz),2.70-2.40 (m, 6H), 2.07-1.98 (m, 1H), 1.74 (t, 1H, J=6.6 Hz); LCMS:purity: 96%; MS (m/e): 451 (MH⁺).

7.3.8795-Fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926949)

To a 0° C. suspension of5-fluoro-N4-(1,2,3,4-tetrahydro-1-oxo-naphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(50 mg, 0.11 mmol) in anhydrous THF (2.0 mL) was addedlithiumborohydride (5 mg, 0.23 mmole). The reaction mixture was warmedto rt, stirred for 8 h, and then quenched with methanol. The reactionmixture was poured into water and then extracted with ethyl acetate.Purification by preparative TLC (5% methanol/dichloromethane) provided5-fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.LCMS: purity: 96%; MS (m/e): 438 (MH⁺).

7.3.880 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine (R926950)

In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and5-amino-2-(methoxycarbonyl)benzofuran were reacted to produceN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.34 (bs, 2H), 8.10-8.07 (m, 2H), 7.78 (t, 1H, J=2.7Hz), 7.66-7.53 (m, 4H), 7.12 (d, 1H, J=9.3 Hz), 3.87 (s, 3H), 3.85 (s,3H); LCMS: purity: 99%; MS (m/e): 443 (MH⁺).

7.3.881N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine(R926951)

In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and5-amino-2,3-dihydro-2-(methoxycarbonyl)benzofuran were reacted toproduceN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.31 (bs, 1H), 10.04 (bs, 1H), 8.21 (d, 1H, J=4.8Hz), 7.75 (t, 1H, J=3.0 Hz), 7.54 (td, 1H, J=3.0 and 9.0 Hz), 7.34 (s,1H), 7.20-7.15 (m, 2H), 6.80 (d, 1H, J=8.1 Hz), 5.38-5.31 (m, 1H), 3.85(s, 3H), 3.69 (s, 3H), 3.49 (dd, 1H, J=11.1 and 16.5 Hz); LCMS: purity:99%; MS (m/e): 446 (MH⁺).

7.3.882N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine(R926953)

In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamineand 5-amino-2,3-dihydro-2-(methoxycarbonyl)benzofuran were reacted toproduceN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.99 (bs, 1H), 9.49 (bs, 1H), 8.18 (d, 1H, J=4.5Hz), 8.08 (t, 1H, J=2.4 Hz), 7.81-7.74 (m, 1H), 7.49 (d, 1H, J=8.1 Hz),7.42 (s, 1H), 7.20 (d, 1H, J=8.1 Hz), 6.78 (d, 1H, J=8.7 Hz), 5.36 (m,1H), 3.80-3.47 (m, 4H), 3.20 (dd, 1H, J=6.0 and 16.5 Hz); LCMS: purity:100%; MS (m/e): 500 (MH⁺).

7.3.883N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-[(N-methylamino)carbonyl]benzofuran-5-yl]-2,4-pyrimidinediamine(R926954)

In a like manner to the preparation ofN4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamine,methylamine hydrogen chloride salt, and diisopropylethylamine werereacted to provideN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-[(N-methylamino)carbonyl]benzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.59 (s, 1H), 9.10 (s, 2H), 8.13-8.10 (m, 1H),8.08-7.98 (m, 1H), 7.82 (d, 1H, J=8.1 Hz), 7.48-7.42 (m, 2H), 7.24 (d,1H, J=8.7 Hz), 6.72 (d, 1H, J=8.7 Hz), 5.06 (dd, 1H, J=5.4 and 9.3 Hz),3.39 (dd, 1H, J=10.5 and 15.6 Hz), 3.15 (dd, 1H, J=6.3 and 15.9 Hz),2.59 (d, 3H, J=4.5 Hz); LCMS: purity: 95%; MS (m/e): 499 (MH⁺).

7.3.884N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-[(N-methylamino)carbonyl]benzofuran-5-yl]-2,4-pyrimidinediamine(R926955)

In a like manner to the preparation ofN4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine,methylamine hydrochloride, and diisopropylethylamine were reacted toprovideN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-[(N-methylamino)carbonyl]benzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.24 (s, 1H), 8.99 (s, 2H), 8.02 (d, 1H, J=3.0 Hz),7.80-7.75 (m, 1H), 7.63 (d, 1H, J=9.0 Hz), 7.47 (s, 1H), 7.23 (d, 1H,J=8.1 Hz), 7.07 (d, 1H, J=8.7 Hz), 6.69 (d, 1H, J=8.1 Hz), 5.05 (dd, 1H,J=2.1 and 9.9 Hz), 3.37 (dd, 1H, J=10.5 and 15.9 Hz), 3.13 (dd, 1H,J=6.0 and 15.9 Hz), 2.59 (d, 3H, J=4.5 Hz); LCMS: purity: 95%; MS (m/e):445 (MH⁺).

7.3.8855-Fluoro-N2-[2,3-dihydro-2-[(N-methylamino)carbonyl]benzofuran-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine(R926956)

In a like manner to the preparation ofN4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine, methylaminehydrochloride, and diisopropylethylamine were reacted to provide5-fluoro-N2-[2,3-dihydro-2-[(N-methylamino)carbonyl]benzofuran-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.1H NMR (DMSO-d₆): δ 9.11 (s, 1H), 8.92 (s, 1H), 8.06-7.98 (m, 1H), 7.97(d, 1H, J=4.2 Hz), 7.60-7.52 (m, 3H), 7.20 (d, 1H, J=8.1 Hz), 6.85 (d,2H, J=8.7 Hz), 6.67 (d, 1H, J=9.0 Hz), 5.04 (dd, 1H, J=5.7 and 9.9 Hz),4.56 (quintet, 1H, J=6.6 Hz), 3.36 (dd, 1H, J=10.5 and 16.5 Hz), 3.10(dd, 1H, J=5.7 and 15.3 Hz), 2.59 (d, 1H, J=4.5 Hz), 1.24 (d, 6H, J=6.6Hz); LCMS: purity: 96%; MS (m/e): 438 (MH⁺).

7.3.886 N2,N4-Bis(3-phenylphenyl)-2,4-pyrimidinediamine (R925809)

In a like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-aminobiphenyl were reacted toprovide N2,N4-Bis(3-phenylphenyl)-2,4-pyrimidinediamine. LCMS: purity:98%; MS (m/e): 415 (MH⁺).

7.3.887 2-Dimethylamine-5-fluoro-N4-(thyrosinyl methyl ester) pyrimidine(R940110)

A solution of 2,4-dichloro-5-fluoropyrimidine (0.03 g, 0.18 mmol) andL-tyrosine methyl ester (0.14 g, 0.7 mmol) in DMF was heated at 100° C.for 3 days. The reaction mixture was cool to room temperature anddiluted with H₂O (10 mL). Upon saturation with sodium chloride it wasextracted with ethyl acetate (3×15 mL), dried over anhydrous sodiumsulfate and the solvent was removed. The resulting residue was filteredthrough a pad of silica gel (200-400 mesh, hexanes/EtOAc 2/8) to obtain2-dimethylamine-5-fluoro-N4-(thyrosinyl methyl ester) pyrimidineR940110. ¹H NMR (CDCl₃): δ 7.76 (1H, d, J=3.2 Hz), 7.00 (2H, d, J=7.5Hz), 6.76 (2H, d, J=7.5 Hz), 5.20 (1H, d, J=7.5 Hz), 4.90 (1H, q, J=5.0Hz), 3.71 (3H, s), 3.14 (2H, m), 3.08 (6H, s); purity: 98%; MS (m/e):335 (M+H).

7.3.8885-Fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine(R940299)

To a solution of2-chloro-5-fluoro-N4-(3-aminocarbonylphenyl)-4-pyrimidineamine (0.050 g,0.18 mmol) in (2 mL) was added3-(methylaminocarbonylmethyleneoxy)aniline (0.1 g, 0.5 mmol). Themixture was heated in a sealed tube at 100° C. for 24 h. The resultingreaction was diluted with H₂O (10 mL), acidified with 2N HCl (pH>2),saturated with sodium chloride and the resulting solid was filtered togive the desired product5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamineR940299. Purification can be done by filtration through a pad of silicagel using 1-5% MeOH in CH₂Cl₂ or by crystallization using an appropriatesolvent system.

Alternatively, the reaction of equimolar amount of2-chloro-5-fluoro-N4-(3-aminocarbonylphenyl)-4-pyrimidineamine and3-(methylaminocarbonylmethyleneoxy) aniline in MeOH in a pressure tubeat 110° C. for 24 h or, in EtOH using microwave at 175° C. for 30-60 minfollowed by aqueous work up, also gave the desired product. ¹H NMR(DMSO-d6): δ 9.79 (1H, s), 9.49 (1H, s), 8.26 (1H, d, J=3.9 Hz), 8.15(1H, t, J=1.8 Hz), 8.10-8.02 (3H, m), 7.68 (1H, d, J=7.5 Hz), 7.51 (1H,t, J=7.9 Hz), 7.48 (1H, s), 7.38 (2H, m), 7.20 (1H, t, J=8.4 Hz), 6.60(1H, d, J=9.3 Hz), 4.45 (2H, s), 2.74 (3H, d, J=4.8 Hz); purity: 95%; MS(m/e): 411 (MH⁺).

7.3.8895-Fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamine(R940300)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to yield5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamineR940300. ¹H NMR (DMSO-d6): δ 9.66 (1H, s), 9.45 (1H, s), 8.21 (1H, d,J=3.9 Hz), 8.06 (2H, m), 8.01 (1H, t, J=2.7 Hz), 7.35 (2H, m), 7.23 (1H,d, J=9 Hz), 7.18 (1H, t, J=8.1 Hz), 6.60 (1H, d, J=7.8 Hz), 4.45 (2H,s), 3.91 (3H, s), 3.84 (3H, s), 2.74 (3H, d, J=3.6 Hz); purity: 93%; MS(m/e): 456 (MH⁺).

7.3.8905-Fluoro-N4-(3-hydroxyphenyl)-N2-(3-methyloxycarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamine(R940301)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-methyloxycarbonyl-4-methoxyaniline were reacted to yield5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-methyloxycarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamineR940301. ¹H NMR (DMSO-d6): δ 9.93 (1H, s), 9.79 (1H, s), 9.54 (1H, s),8.26 (1H, s, J=4.5 Hz), 7.92 (1H, s), 7.81 (1H, dd, J=9.3 Hz, J=2.7 Hz),7.32 (1H, d, J=8.1 Hz), 7.20-7.13 (3H, m), 6.64 (1H, d, J=8.1 Hz), 3.89(3H, s), 3.84 (3H, s); purity: 97%; MS (m/e): 385 (MH⁺).

7.3.8915-Fluoro-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamine(R940304)

A mixture of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine(0.15 g, 0.4 mmol), methylamine hydrochloride (0.324 g, 48 mmol) anddiisopropylethylamine (0.84 mL, 48 mmol) in MeOH (2 mL) was heated in asealed tube at 100° C. for 24 h (followed by TLC). The reaction wascooled to room temperature and diluted with H₂O (20 mL). The solid wasfiltered, washed with H₂O and dried to obtain5-fluoro-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamineR940304. ¹H NMR (DMSO-d6): δ 10.65 (1H, s), 8.48 (1H, s), 8.29 (2H, m),7.93 (1H, m), 7.28 (1H, d, J=9 Hz), 4.00 (3H, s), 2.94 (3H, s), 2.90(3H, d, J=4.5 Hz); purity: 90%; MS (m/e): 306 (MH⁺);

7.3.8925-Fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamine(R940306)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to yield5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamineR940306. ¹H NMR (DMSO-d6): δ 9.28 (1H, s), 9.21 (1H, s), 8.12 (1H, d,J=3.9 Hz), 8.06 (1H, d, J=2.7 Hz), 7.99 (1H, m), 7.89 (1H, dd, J=9.3 Hz,J=2.7 Hz), 7.52 (1H, q, J 4.9 Hz), 7.41 (1H, t, J 2.1 Hz), 7.37 (1H, d,J 7.5 Hz), 7.10 (1H, t, J=8.1 Hz), 6.83 (1H, d, J=9 Hz), 6.53 (1H, dd,J=8.1 Hz, J=1.8 Hz), 4.40 (2H, s), 3.82 (3H, s), 2.96 (3H, d, J=5.1 Hz),2.73 (3H, d, J=4.5 Hz); purity: 93%; MS (m/e): 455 (MH⁺).

7.3.893(R)—N2-[3-(dihydroxypropylaminocarbonylmethyleneoxy)-phenyl]-5-fluoro-N4-(3-isopropylphenyl)-2,4-pyrimidinediamine(R940307)

In like manner to the preparation of5-fluoro-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamine,5-fluoro-N4-(3-isopropylphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand (R)-3-amino-1,2-propanediol were reacted to give(R)—N2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl)-5-fluoro-N4-(3-isopropylphenyl)-2,4-pyrimidinediamineR940307. ¹H NMR (DMSO-d6): δ 9.96 (1H, s), 9.80 (1H, s), 8.29 (1H. d,J=4.5 Hz), 7.98 (1H, t, J=5.5 Hz), 7.77 (1H, d, J=7.2 Hz), 7.57 (1H, s),7.37 (1H, t, J=7.8 Hz), 7.30-7.22 (3H, m), 7.12 (1H, d, J=7.8 Hz), 6.70(1H, d, J=7.5 Hz), 4.47 (2H, s), 3.62 (1H, m), 3.38 (3H, m), 3.15 (1H,m), 2.94 (1H, quint, J=6.9 Hz), 1.27 (6H, d, 6.9 Hz); purity: 99%; MS(m/e): 469 (M), 470 (MH⁺).

7.3.894N4-(3-tert-Butylpheny)-5-fluoro-N2-[3-(1,1-dimethyl-2-hydroxyethylaminocarbonylmethyleneoxy)-phenyl]-2,4-pyrimidinediamine(R940308)

In like manner to the preparation of5-fluoro-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamine,N4-(3-tert-butylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand 2-amino-2-methyl-1-propanol were reacted to giveN4-(3-tert-butylpheny)-5-fluoro-N2-[3-(1,1-dimethyl-2-hydroxyethylaminocarbonylmethyleneoxy)-phenyl]-2,4-pyrimidinediamineR940308. ¹H NMR (DMSO-d6): δ 9.38 (1H, s), 9.28 (1H, s), 8.20 (1H, d,J=3.9 Hz), 7.99 (1H, d, J=7.5 Hz), 7.60 (1H, t, J=2.1 Hz), 7.46 (1H, s),7.37 (2H, t, J=7.9 Hz), 7.30 (1H, s), 7.19 (2H, t, J=7.9 Hz), 6.56 (1H,dd, J=7.5 Hz, J=1.5 Hz), 5.06 (1H, t, J=5.7 Hz), 4.37 (2H, s), 3.40 (2H,m), 1.36 (9H, s), 1.32 (6H, s); purity: 93%; MS (m/e): 482 (MH⁺).

7.3.895N4-(3-Aminomethylenephenyl)-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R940309)

A mixture ofN4-[3-(N-tert-butoxycarbonyl-N-aminomethylene)-phenyl]-2-chloro-5-fluoro-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline in MeOH was heated in asealed tube at 100° C. for 12 h. The reaction was cool to roomtemperature and the solvent was removed under reduce pressure. Theresulting residue was filtered through a pad of silica gel (200-400mesh, EtOAc/MeOH (2M NH₃) 95:5) to obtain the desired productN4-(3-aminomethylenephenyl)-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineR940309. ¹H NMR (DMSO-d6): δ 9.41 (1H, s), 9.23 (1H, s), 8.20 (1H, d,J=3.9 Hz), 8.00 (1H, m), 7.78 (1H, s), 7.72 (1H, d, J=7.2 Hz), 7.46 (1H,s), 7.42-7.33 (2H, m), 7.21 (1H, t, J=7.8 Hz), 7.14 (1H, d, J=7.8 Hz),6.59 (1H, dd, J=8.1 Hz, J=2.4 Hz), 4.42 (2H, s), 3.79 (2H, s), 2.74 (3H,d, J=4.8 Hz); purity: 98%; MS (m/e): 397 (MH⁺).

7.3.896N4-[3-(2-(N4-(3-aminomethylenephenyl)-5-fluoro-4-pyrimidineamine)-N-methylaminomethylene)-phenyl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidineamine(R940311)

A mixture ofN4-[3-(N-methylaminomethylene)-phenyl]-2-chloro-5-fluoro-4-pyrimidineamine(0.05 g, 0.18 mmol) and 3-(methylaminocarbonylmethyleneoxy)aniline (0.04g, 0.22 mmol) in EtOH (0.5 mL),was heated at 175° C. for 35 min usingmicrowave. An aqueous work up gave the desiredN4-[3-(2-(N4-(3-aminomethylenephenyl)-5-fluoro-4-pyrimidineamine)-N-methylaminomethylene)-phenyl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidineamineR940311. ¹H NMR (DMSO-d6): δ 9.48 (1H, s), 9.31 (1H, s), 9.26 (1H, s),8.20 (1H, d, J=3.6 Hz), 8.10-8.05 (4H, m), 7.62 (1H, s), 7.49 (2H, m),7.41 (1H, t, J=8.1 Hz), 7.36 (2H, m), 7.22 (1H, t, J=8.4 Hz), 7.17 (1H,t, J=8.4 Hz), 7.06 (1H, d, J=7.5 Hz), 6.59 (1H, dd, J=8.4 Hz, J=2.4 Hz),6.54 (1H, dd, J=7.8 Hz, J=2.4 Hz), 4.93 (2H, s), 4.46 (2H, s), 4.45 (2H,s), 3.28 (3H, d, J=3 Hz), 2.73 (6H, m); purity: 98%; MS (m/e): 684 (M),685 (MH⁺).

7.3.8975-Fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-iso-propylaminocarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamine(R940312)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-N-iso-propylaminomethylene-4-methoxyphenyl)-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to produce5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-iso-propylaminocarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamineR940312. ¹H NMR (DMSO-d6): δ 10.09 (1H, s), 9.88 (1H, s), 8.25 (1H, d,J=4.8 Hz), 8.07 (1H, d, J=2.7 Hz), 8.05 (1H, m), 7.81 (1H, dd, J=9 Hz,J=2.7 Hz), 7.63 (1H, s), 7.25 (2H, m), 7.17 (1H, t, J=8.25 Hz), 6.91(1H, d, J=9 Hz), 6.68 (1H, d, J=8.1 Hz), 4.42 (2H, s), 3.85 (1H, m),3.81 (3H, s), 2.72 (3H, d, J=4.2 Hz), 1.30 (6H, d, J=6 Hz); purity: 97%;MS (m/e): 483 (MH⁺).

7.3.8985-Fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-[3-(N-morpholinomethylene)-4-methoxyphenyl]-2,4-pyrimidinediamine(R940314)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,N2-chloro-5-fluoro-N4-[3-(N-morpholinomethylene)-4-methoxyphenyl]-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to produce5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-[3-(N-morpholinomethylene)-4-methoxyphenyl]-2,4-pyrimidinediamineR940314. ¹H NMR (DMSO-d6): δ 9.33 (1H, s), 9.21 (1H, s), 8.15 (1H, d,J=3.6 Hz), 8.04 (1H, d, J=4.8 Hz), 7.82 (1H, dd, J=9 Hz, J=2.7 Hz), 7.57(1H, d, J=3 Hz), 7.47 (1H, t, J=1.95 Hz), 7.34 (1H, m), 7.18 (1H, t,J=8.1 Hz), 7.04 (1H, d, J 9 Hz), 6.56 (1H, dd, J=8.4 Hz, J=2.1 Hz), 4.40(2H, s), 3.86 (3H, s), 3.63 (4H, t, J=4.5 Hz), 3.53 (2H, s), 2.74 (3H,d, J=4.5 Hz), 2.46 (4H, m); purity: 97%; MS (m/e): 497 (MH⁺).

7.3.899N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[3-(N-morpholinomethylene)-4-methoxyphenyl]-2,4-pyrimidinediamine(R940316)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,N2-chloro-5-fluoro-N4-[3-(N-morpholinomethylene)-4-methoxyphenyl]-4-pyrimidineamineand 4-amino-2-chloro-6-methylphenol were reacted to produceN2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[3-(N-morpholinomethylene)-4-methoxyphenyl]-2,4-pyrimidinediamineR940316. ¹H NMR (DMSO-d6): δ 9.28 (1H, s), 9.01 (1H, s), 8.65 (1H, s),8.11 (1H, d, J=3.9 Hz), 7.76 (1H, dd, J=9 Hz, J=3 Hz), 7.61 (1H, d,J=2.4 Hz), 7.50 (1H, d, J=2.7 Hz), 7.30 (1H, d, J=2.1 Hz), 7.04 (1H, d,J=8.7 Hz), 3.87 (3H, s), 3.63 (4H, t, J=4.3 Hz), 3.52 (2H, s), 2.45 (4H,m), 2.17 (3H, s); purity: 97%; MS (m/e): 474 (MH⁺).

7.3.900N4-(3-N-methylaminomethylenephenyl)-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R940317)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,N4-[3-(N-tert-butoxycarbonyl-N-methylaminomethylene)-phenyl]-2-chloro-5-fluoro-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to produceN4-(3-N-methylaminomethylenephenyl)-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineR940317. ¹H NMR (DMSO-d6): δ 9.41 (1H, s), 9.31 (1H, s), 9.29 (1H, s),8.20 (1H, d, J=3 Hz), 8.05 (1H, m), 7.80 (1H, d, J=7.8 Hz), 7.74 (1H,s), 7.45-7.35 (3H, m), 7.21 (1H, t, J=8.1 Hz), 7.13 (1H, d, J=7.5 Hz),6.59 (1H, d, J=9.6 Hz), 4.43 (2H, s), 3.71 (2H, s), 2.75 (3H, d, J=4.2Hz), 2.35 (3H, s); purity: 83.9%; MS (m/e): 411 (MH⁺).

7.3.901N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[3-(N-piperazinomethylene)-4-methoxyphenyl]-2,4-pyrimidinediamine(R940318)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,N4-[3-(N-piperazinomethylene)-4-methoxyphenyl]-2-chloro-5-fluoro-4-pyrimidineamineand 4-amino-2-chloro-6-methylphenol were reacted to produceN2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[3-(N-piperazinomethylene)-4-methoxyphenyl]-2,4-pyrimidinediamineR940318. ¹H NMR (DMSO-d6): δ 9.27 (1H, s), 9.00 (1H, s), 8.10 (1H, d,J=3.6 Hz), 7.75 (1H, dd, J=8.7 Hz, J=2.7 Hz), 7.61 (1H, d, J=2.4 Hz),7.49 (1H, d, J=2.4 Hz), 7.31 (1H, d, J=2.4 Hz), 7.03 (1H, d, J=9 Hz),3.86 (3H, s), 3.49 (2H, s), 2.75 (4H, t, J=4.65 Hz), 2.39 (4H, m), 2.17(3H, s); purity: 95%; MS (m/e): 473 (MH⁺).

7.3.902N4-(3-(N-tert-Butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxyphenyl)-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine (R940319)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,N4-(3-(N-tert-butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to produceN4-(3-(N-tert-butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxyphenyl)-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineR940319. ¹H NMR (DMSO-d6): δ 9.44 (1H, s), 8.95 (1H, s), 8.15 (1H, d,J=3.6 Hz), 8.06 (1H, m), 7.83 (1H, m), 7.74 (1H, m), 7.56 (1H, m), 7.37(1H, m), 7.20 (1H, t, J=7.9 Hz), 7.02 (1H, d, J=9.3 Hz), 6.57 (1H, d,J=7.8 Hz), 4.44 (2H, s), 4.42 (1H, m), 4.33 (2H, s), 3.89 (3H, s), 2.74(3H, d, J=4.8 Hz), 1.52-1.30 (9H, m), 1.16 (6H, d, J=6.9 Hz); purity:98%; MS (m/e): 569 (MH⁺).

7.3.903N4-(3-N,N-Dimethylaminomethylene-4-methoxyphenyl)-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R940321)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3-N,N-dimethylaminomethylene-4-methoxyphenyl)-5-fluoro-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to produceN4-(3-N,N-dimethylaminomethylene-4-methoxyphenyl)-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineR940321. ¹H NMR (DMSO-d6): δ 9.32 (1H, s), 9.23 (1H, s), 8.14 (1H, d,J=3.9 Hz), 8.05 (1H, m), 7.83 (1H, dd, J=8.7 Hz, J=2.4 Hz), 7.55 (1H, d,J=2.4 Hz), 7.45 (1H, s), 7.36 (1H, d, J=8.4 Hz), 7.18 (1H, t, J=8.1 Hz),7.03 (1H, d, J=9 Hz), 6.56 (1H, dd, J=7.2 Hz, J=1.5 Hz), 4.41 (2H, s),3.86 (3H, s), 2.73 (3H, d, J=4.5 Hz), 2.24 (6H, s); purity: 91.8%; MS(m/e): 455 (MH⁺).

7.3.904N4-[(2,2-Dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R940323)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to produceN4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineR940323. ¹H NMR (DMSO-d6): δ 10.70 (1H, s), 9.45 (1H, s), 9.19 (1H, s),8.17 (1H, d, J=3.9 Hz), 8.05 (1H, m), 7.43-7.34 (4H, m), 7.17 (1H, t,J=8.25 Hz), 6.98 (1H, d, J=8.4 Hz), 6.56 (1H, dd, J=7.8 Hz, J=2.1 Hz),4.25 (2H, s), 2.74 (3H, d, J=4.5 Hz), 1.5 (6H, s); purity: 98.7%; MS(m/e): 467 (MH⁺).

7.3.905N4-[3-Dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazin-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R940337)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[3-dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazin-6-yl]-5-fluoro-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to produceN4-[3-dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazin-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineR940337. ¹H NMR (DMSO-d6): δ 9.28 (1H, s), 9.20 (1H, s), 8.34 (1H, dd,J=4.8 Hz, J=1.2 Hz), 8.14 (1H, d, J=3.8 Hz), 8.03 (1H, m), 7.64-7.60(2H, m), 7.51-7.46 (3H, m), 7.37 (1H, d, J=8.4 Hz), 7.17 (1H, t, J=8.1Hz), 6.94-6.91 (2H, m), 6.55 (1H, dd, J=8.4 Hz, J=3 Hz), 4.42 (2H, s),3.93 (2H, s), 2.74 (3H, d, J=4.5 Hz), 1.32 (6H, s); purity: 98.2%; MS(m/e): 530 (MH⁺);

7.3.906N4-[(2,2-Dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(1-methylindazolin-5-yl)-2,4-pyrimidinediamine(R940338)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand 5-amino-1-methyl-1-indazole were reacted to produceN4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(1-methylindazolin-5-yl)-2,4-pyrimidinediamineR940338. ¹H NMR (DMSO-d6): δ 10.73 (1H, s), 9.39 (1H, s), 9.17 (1H, s),8.21 (1H, s), 8.16 (1H, d, J=3.9 Hz), 7.87 (1H, s), 7.56 (2H, m), 7.41(1H, m), 7.32 (1H, s), 7.00 (1H, d, J=8.4 Hz), 4.07 (3H, s), 1.51 (6H,s); purity: 99.2%; MS (m/e): 434 (MH⁺).

7.3.907N4-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R921303)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to produceN4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineR921303. ¹H NMR (DMSO-d6): δ 12.05 (1H, s), 9.67 (1H, s), 9.27 (1H, s),8.24 (1H, d, J=3.6 Hz), 8.05 (1H, m), 7.73-7.68 (1H, m), 7.56 (1H, t,J=2.7 Hz), 7.50 (1H, s), 7.36 (2H, d, J=8.7 Hz), 7.19 (1H, t, J=8.2 Hz),6.58 (1H, dd, J=8.4 Hz, J=2.4 Hz), 4.34 (2H, s), 2.74 (3H, d, J=4.5 Hz);¹⁹F NMR (DMSO-d6): δ −21643, −46385; purity: 100%; MS (m/e): 475 (MH⁺).

7.3.908N4-[(2,2-Dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-7-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R940345)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-7-yl]-5-fluoro-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to produceN4-[(2,2-dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-7-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineR940345. ¹H NMR (DMSO-d6): δ 11.23 (1H, s), 9.69 (1H, s), 9.54 (1H, s),8.50 (1H, s), 8.25 (1H, d, J=3.3 Hz), 8.06 (1H, m), 7.96 (1H, t, J=2.5Hz), 7.41-7.36 (2H, m), 7.24 (1H, t, J=8.25 Hz), 6.34 (1H, d, J=8.7 Hz),4.47 (2H, s), 2.74 (3H, d, J=3.3 Hz), 1.53 (6H, s); purity: 98.4%; MS(m/e): 468 (MH⁺).

7.3.909N4-[(2,2-Dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R940346)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand 3-aminophenol were reacted to produceN4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamineR940346. ¹H NMR (DMSO-d6): δ 10.75 (1H, s), 8.25 (1H, d, J=4.5 Hz),7.42-7.37 (1H, m), 7.34 (1H, s), 7.10 (3H, m), 7.00 (1H, d, J=8.4 Hz),6.53 (1H, m), 1.50 (6H, s); purity: 97.5%; MS (m/e): 396 (MH⁺).

7.3.910N4-[(2,2-Dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R940347)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to produceN4-[(2,2-dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineR940347. ¹H NMR (DMSO-d6): δ 11.20 (1H, s), 9.46 (1H, s), 8.26 (1H, d,J=3.6 Hz), 8.06 (1H, s), 7.71 (1H, m), 7.49 (1H, d, J=8.4 Hz), 7.45 (1H,s), 7.38 (1H, d, J=9 Hz), 7.21 (1H, t, J=8.1 Hz), 6.61 (1H, d, J=8.7Hz), 4.47 (2H, s), 2.74 (3H, s), 1.52 (6H, s); purity: 100%; MS (m/e):468 (MH⁺).

7.3.911N4-[3-Dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazin-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R940348)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[3-dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazin-6-yl]-5-fluoro-4-pyrimidineamineand 3-aminophenol were reacted to produceN4-[3-dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazin-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamineR940348. ¹H NMR (DMSO-d6): δ 9.25 (1H, s), 9.23 (1H, s), 9.02 (1H, s),8.34 (1H, d, J=4.5 Hz), 8.11 (1H, d, J=3.3 Hz), 7.62 (2H, m), 7.52 (2H,m), 7.22 (1H, s), 7.19 (1H, d, J=7.5 Hz), 7.03 (1H, t, J=7.9 Hz), 6.93(2H, m), 6.38 (1H, d, J=7.8 Hz), 3.93 (2H, s), 1.32 (6H, s); purity:96.5%.

7.3.912N4-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R940349)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand 3-aminophenol were reacted to produceN4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamineR940349. ¹H NMR (DMSO-d6): δ 12.03 (1H, s), 9.63 (1H, s), 9.26 (1H, s),9.09 (1H, s), 8.21 (1H, d, J=3.6 Hz), 7.70 (1H, dd, J=9 Hz, J=2.4 Hz),7.59 (1H, d, J=2.7 Hz), 7.34 (1H, d, J=9.3 Hz), 7.26 (1H, s), 7.16 (1H,d, J=7.8 Hz), 7.04 (1H, t, J=8.2 Hz), 6.41 (1H, d, J=10.2 Hz); ¹⁹F NMR(DMSO-d6): δ −21646, −46516; purity: 95.8%; MS (m/e): 404 (MH⁺);

7.3.913N2,N4-[(2,2-Dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-2,4-pyrimidinediamine(R940350)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-dimethyl-4H-5-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand 6-amino-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one were reacted toproduceN2,N4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-2,4-pyrimidinediamineR940350. ¹HNMR (DMSO-d6): δ 10.68 (1H, s), 10.62 (1H, s), 9.38 (1H, s),9.04 (1H, s), 8.11 (1H, d, J=3.6 Hz), 7.46 (1H, dd, J=8.1 Hz, J=1.8 Hz),7.33-7.26 (3H, m), 6.95 (1H, d, J=8.7 Hz), 6.84 (1H, d, J=8.4 Hz), 1.49(6H, s), 1.45 (6H, s); purity: 95.4%; MS (m/e): 479 (MH⁺).

7.3.914N2-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-N4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-2,4-pyrimidinediamine(R940351)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one were reacted toproduceN2-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-N4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-2,4-pyrimidinediamineR940351. ¹H NMR (DMSO-d6): δ 11.99 (1H, s), 10.74 (1H, s), 9.64 (1H, s),9.50 (1H, s), 8.19 (1H, d, J=3.9 Hz), 7.50 (2H, m), 7.43 (1H, dd, J=8.4Hz, J=1.8 Hz), 7.32 (1H, s), 7.20 (1H, d, J=9.3 Hz), 6.98 (1H, d, J=8.7Hz), 1.49 (6H, s); purity: 94.77%; MS (m/e): 487 (MH⁺).

7.3.915N2,N4-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-2,4-pyrimidinediamine(R940352)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one were reacted toproduceN2,N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-2,4-pyrimidinediamineR940352. ¹H NMR (DMSO-d6): δ 12.08 (1H, s), 12.00 (1H, s), 9.72 (1H, s),9.44 (1H, s), 8.23 (1H, d, J=3.6 Hz), 7.73 (1H, dd, J=11.1 Hz, J=1.5Hz), 7.6 (1H, s), 7.56 (1H, s), 7.51 (1H, dd, J=9.6 Hz, J=2.4 Hz), 7.35(1H, d, J=9 Hz), 7.24 (1H, d, J=8.7 Hz); ¹⁹F NMR (DMSO-d6): δ −21670,−21722, −4651; purity: 100%; MS (m/e): 495 (MH⁺).

7.3.916N4-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine(R940353)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand methyl 5-aminobenzofuran-2-carboxylate were reacted to produceN4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamineR940353. ¹H NMR (DMSO-d6): δ 12.05 (1H, s), 9.69 (1H, s), 9.43 (1H, s),8.28 (1H, s), 8.25 (1H, d, J=3.6 Hz), 7.40-7.64 (4H, m), 7.54 (1H, s),7.38 (1H, d, J=9 Hz), 3.97 (3H, s); ¹⁹F NMR (DMSO-d6): δ −21707, −46489;purity: 97.77%; MS (m/e): 486 (MH⁺).

7.3.917N4-[(2,2-Dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine(R940354)

In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand methyl 5-aminobenzofuran-2-carboxylate were reacted to produceN4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamineR940354. ¹H NMR (DMSO-d6): δ 10.75 (1H, s), 9.67 (1H, s), 9.53 (1H, s),8.25 (1H, s), 8.21 (1H, d, J=4.2 Hz), 7.66 (2H, s), 7.59 (1H, s), 7.31(1H, d, J=8.7 Hz), 7.26 (1H, s), 7.03 (1H, d, J=8.1 Hz), 3.97 (3H, s),1.52 (6H, s); purity: 95.58%; MS (m/e): 478 (MH⁺).

7.3.918N2,N4-Bis(3-N-acetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine(R950244)

N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,dimethylaminopyridine (DMAP) and acetic anhydride were refluxed inpyridine for 1 hour. The mixture was cooled to room temperature,concentrated, and the residue was subjected to column chromatography onsilica gel (CHCl₃:Acetone, 2:1) to giveN2,N4-bis(3-N-acetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine.¹H NMR (MeOD, 300 MHz): δ 8.65 (d, 1H, J=2.4 Hz), 7.15-7.58 (m, 8H),2.24 (s, 3H), 2.22 (s, 3H), 2.14 (s, 3H), 2.09 (s, 3H); LCMS: ret. time:17.03 min.; purity: 87.0%; MS (m/e): 478.89 (MH⁺).

7.3.919N4-(3-N,N-Diacetylaminophenyl)-N2-(3-N-acetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine(R950245)

N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,dimethylaminopyridine (DMAP) and acetic anhydride were refluxed inpyridine for 1 hour. The mixture was cooled to room temperature,concentrated, and the residue was subjected to column chromatography onsilica gel (CHCl₃:Acetone, 2:1) to giveN4-(3-N,N-diacetylaminophenyl)-N2-(3-N-acetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine.¹H NMR (MeOD, 300 MHz): δ 8.65 (d, 1H, J=2.4 Hz), 7.03-7.66 (m, 8H),2.21 (s, 6H), 2.14 (s, 3H), 2.12 (s, 3H), 2.08 (s, 3H); LCMS: ret. time:19.27 min.; purity: 92.6%; MS (m/e): 521.01 (MH⁺).

7.3.920N4-(3-N-Acetylaminophenyl)-N2-(3-N,N-diacetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine(R950246)

N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,dimethylaminopyridine (DMAP) and acetic anhydride were refluxed inpyridine for 1 hour. The mixture was cooled to room temperature,concentrated, and the residue was subjected to column chromatography onsilica gel (CHCl₃:Acetone, 2:1) to giveN4-[3-N-acetylaminophenyl]-N2-(3-N,N-diacetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine.¹H NMR (MeOD, 300 MHz): δ 8.66 (d, 1H, J=2.4 Hz), 6.88-7.57 (m, 8H),2.22 (s, 6H), 2.11 (s, 3H), 2.10 (s, 3H), 2.09 (s, 3H); LCMS: ret. time:18.89 min.; purity: 83.0%; MS (m/e): 520.97 (MH⁺).

7.3.921N2,N4-Bis(3-N,N-diacetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine(R950247)

N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,dimethylaminopyridine (DMAP) and acetic anhydride were refluxed inpyridine for 1 hour. The mixture was cooled to room temperature,concentrated, and the residue was subjected to column chromatography onsilica gel (CHCl₃:Acetone, 2:1) to giveN2,N4-bis(3-N,N-diacetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine.¹H NMR (MeOD, 300 MHz): δ 8.58 (d, 1H, J=2.4 Hz), 6.75-7.53 (m, 8H),2.04 (s, 3H), 2.03 (s, 3H), 2.01 (s, 6H), 1.99 (s, 6H); LCMS: ret. time:21.51 min.; purity: 91.8%; MS (m/e): 563.00 (MH⁺).

7.3.922N4-(3-Nitrophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950261)

A mixture of equimolar amounts of2-chloro-N4-(3-nitrophenyl)-5-fluoro-4-aminopyridine and3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in a pressure tubeat 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20 minfollowed by aqueous work up gaveN4-(3-nitrophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 92.7%; MS (m/e): 412.94 (MH⁺).

7.3.923N4-(3-Aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineHCl salt (R950262)

N4-(3-Nitrophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine and Pd/C 10% (50% water content) weresuspended in EtOH-10% aqueous HCl (1:1) and hydrogenated in a Parrapparatus for 2 hours (22° C., 50 psi). The suspension was filtered overcelite and carefully washed with MeOH. The combined filtrates wereconcentrated under reduced pressure to give the HCl salt ofN4-(3-aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 92.7%; MS (m/e): 383.07 (M-C1⁺, 100).

7.3.924N4-(3-Aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950263)

The HCl salt ofN4-(3-aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminewas neutralized with aqueous sodium carbonate solution and extractedwith EtOAc. The organic phase was dried and concentrated to giveN4-(3-aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a pale yellow solid. ¹H NMR (DMSO): δ 10.00 (s, 1H), 9.92 (s, 1H),8.07 (d, 1H, J=2.4 Hz), 8.15 (bs, 2H), 7.91-8.07 (m, 3H), 7.08-7.21 (m,5H), 6.56 (d, 1H, J=7.2 Hz), 4.32 (s, 2H), 2.72 (d, 3H, J=4.8 Hz); LCMS:purity: 92.7%; MS (m/e): 383.17 (MH⁺, 100).

7.3.925N4-(3-Bis-N-methylaminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950264)

A solution ofN4-(3-aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein DME-DMF (1:1) was treated with 10 equivalents of MeI and sodiumbicarbonate. The mixture was stirred for 1.5 hours at 70° C. andpurified by flash chromatography on silica gel to giveN4-(3-bis-N-methylaminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 90.2%; MS (m/e): 411.04 (MH⁺, 100).

7.3.926N4-(3-N-Hydroxyethylaminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950265)

A solution ofN4-(3-aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein DME-DMF (1:1) was treated with 10 equivalents of 2-bromoethanol andsodium bicarbonate. The mixture was stirred for 16 hours at 70° C. andpurified by flash chromatography on silica gel to giveN4-(3-N-hydroxyethylaminophenyl)-5-fluoro. LCMS: purity: 90.2%; MS(m/e): 427.33 (MH⁺, 100).

7.3.927N4-(3-Bis(N-hydroxyethyl)aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950266)

A solution ofN4-(3-aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein DME-DMF (1:1) was treated with 10 equivalents of 2-bromoethanol andsodium bicarbonate. The mixture was stirred for 16 hours at 70° C. andpurified by flash chromatography on silica gel to giveN4-(3-bis(N-hydroxyethyl)aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 94.2%; MS (m/e): 471.46 (MH⁺, 100).

7.3.928N4-(3-N-Methylaminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950267)

A solution ofN4-(3-aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein DME-DMF (1:1) was treated with 10 equivalents of MeI and sodiumbicarbonate. The mixture was stirred for 1.5 hours at 70° C. andpurified by flash chromatography on silica gel to giveN4-(3-N-methylaminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 92.3%; MS (m/e): 397.02 (MH⁺, 100).

7.3.929N4-(3-Carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950290)

A mixture of equimolar amounts of2-chloro-N4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-4-aminopyridine and3-ethoxycarbonylmethyleneoxyaniline in MeOH in a pressure tube at 110°C. for 24 h or in EtOH using microwave at 175° C. for 10-20 min followedby aqueous work up gaveN4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 97.8%; MS (m/e): 443.20 (MH⁺).

7.3.930N4-(3-Carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-carboxymethyleneoxyphenyl]-2,4-pyrimidinediamine(R950291)

The reaction ofN4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(0.1 g) and LiOH (10 equivalents) in MeOH:water (1:1, v/v) for 1 h atroom temperature followed by treatment with aqueous HCl gave the solid.The resulting solid was filtered, washed with water and dried to giveN4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-carboxymethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 91.5%; MS (m/e): 415.16 (MH⁺).

7.3.931N4-(3-Methoxycarbonyl-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950293)

A solution ofN4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein dry MeOH was treated with a 4 M solution of HCl in dioxane. Themixture was stirred for 1 hour at 22° C., concentrated to dryness andpurified by flash chromatography on silica gel to giveN4-(3-methoxycarbonyl-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 96.8%; MS (m/e): 457.25 (MH⁺).

7.3.932N4-(4-Methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950294)

A mixture of equimolar amounts of2-chloro-N4-(4-methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-4-aminopyridineand 3-ethoxycarbonylmethyleneoxyaniline in EtOH using microwave at 175°C. for 10-20 min followed by aqueous work up gaveN4-(4-methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 92.1%; MS (m/e): 469.26 (MH⁺).

7.3.933N4-(4-Methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-methoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950295)

A mixture of equimolar amounts of2-chloro-N4-(4-methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-4-aminopyridineand 3-ethoxycarbonylmethyleneoxyaniline in MeOH in a pressure tube at110° C. for 24 h followed by aqueous work up gaveN4-(4-methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-methoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 87.6%; MS (m/e): 455.26 (MH⁺).

7.3.934N4-(4-Ethoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950296)

A solution ofN4-(4-ethoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein EtOH was treated with the HCl salt of methylamine. The mixture wasstirred for 4 hours at 100° C., concentrated to dryness and purified byflash chromatography on silica gel to giveN4-(4-ethoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 87.4%; MS (m/e): 468.29 (MH⁺).

7.3.935N4-(4-Carboxyethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950344)

A mixture of equimolar amounts of2-chloro-N4-(4-carboxyethyleneoxyphenyl)-5-fluoro-4-aminopyridine and3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in a pressure tubeat 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20 minfollowed by aqueous work up gaveN4-(4-carboxyethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 97.8%; MS (m/e): 456.32 (MH⁺).

7.3.936N4-(2,3-Dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950345)

A solution ofN4-(4-Methoxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein TfOH was heated for 2 hours at 100° C. Aqueous work up followed byflash chromatography on silica gel gaveN4-(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 92.2%; MS (m/e): 435.95 (MH⁺).

7.3.937N4-(4-Methoxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950346)

A solution ofN4-(4-carboxyethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein dry MeOH was treated with a 4 M solution of HCl in dioxane. Themixture was stirred for 1 hour at 22° C., concentrated to dryness andpurified by flash chromatography on silica gel to giveN4-(4-methoxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 85.2%; MS (m/e): 468.01 (MH⁺).

7.3.938N4-(4-Hydroxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950347)

The reaction ofN4-(4-methoxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand LiOH (10 equivalents) in MeOH:water (1:1, v/v) for 1 h at roomtemperature followed by treatment with aqueous HCl gave a pale yellowsolid. The resulting solid was filtered, washed with water and dried togiveN4-(4-hydroxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 94.7%; MS (m/e): 382.03 (MH⁺).

7.3.939N4-(2,3-Dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950348)

A mixtureN4-(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand hydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN4-(2,3-dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 89.5%; MS (m/e): 451.00 (MH⁺).

7.3.940N4-(4-Hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950349)

A solution ofN4-(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein dry MeOH was treated with a sodiumcyanoborohydride. The mixture wasstirred for 1 hour at 22° C., concentrated to dryness and purified byflash chromatography on silica gel to giveN4-(4-Hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ 9.19 (s, 1H), 9.09 (s, 1H), 8.03 (d,1H, J=2.4 Hz), 7.28-7.93 (m, 5H), 7.07 (t, 1H, J=7.2 Hz), 6.71 (d, 1H,J=7.2 Hz), 6.44 (dd, 1H, J=2.6, 7.2 Hz), 5.31 (d, 1H, J=5.1 Hz),4.14-4.59 (m, 3H), 4.30 (s, 2H), 2.63 (d, 3H, J=4.8 Hz), 1.82-2.03 (m,2H); LCMS: purity: 93.3%; MS (m/e): 440.15 (MH⁺).

7.3.941N4-(2,3-Dihydro-4-O-methyloxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950356)

A mixtureN4-(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand methoxyamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN4-(2,3-dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine as a white solid. LCMS: purity: 85.5%;MS (m/e): 465.10 (MH⁺).

7.3.942N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950368)

A mixtureN4-(4-azido-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand Pd/C (10%) in MeOH was hydrogenated at 22° C. for 6 hours (40 psi).The mixture was filtered and concentrated to dryness to giveN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ 9.60 (s, 1H), 9.46 (s, 1H), 8.73 (bs,3H), 8.00-8.10 (m, 3H), 7.47 (s, 1H), 7.42 (m, 1H), 7.29 (d, 1H, J=7.2Hz), 7.11 (t, 1H, J=7.2 Hz), 6.82 (d, 1H, J 7.0 Hz), 6.46 (m, 1H),4.23-4.46 (m, 3H), 4.31 (s, 3H), 2.63 (d, 3H, J=4.8 Hz), 2.09-2.29 (m,2H); LCMS: purity: 97.6%; MS (m/e): 438.98 (MH⁺).

7.3.943N4-(3-Methylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950371)

A mixture of equimolar amounts of2-chloro-N4-(3-methylcarbonylphenyl)-5-fluoro-4-aminopyridine and3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in a pressure tubeat 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20 minfollowed by aqueous work up gaveN4-(3-methylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ 10.16 (s, 1H), 9.82 (s, 1H), 8.24 (d,1H, J=2.4 Hz), 8.15 (s, 1H), 7.91-8.07 (m, 2H), 7.70 (d, 1H, J=7.0 Hz),7.49 (t, 1H, J=7.2 Hz), 7.08-7.21 (m, 3H), 6.56 (d, 1H, J=7.2 Hz), 4.30(s, 3H), 2.62 (d, 3H, J=4.8 Hz), 2.48 (s, 3H); LCMS: purity: 93.8%; MS(m/e): 410.50 (MH⁺).

7.3.944N4-(3-Phenylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950372)

A mixture of equimolar amounts of2-chloro-N4-(3-phenylcarbonylphenyl)-5-fluoro-4-aminopyridine and3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in a pressure tubeat 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20 minfollowed by aqueous work up gaveN4-(3-phenylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 86.0%; MS (m/e): 472.50 (MH⁺).

7.3.945N4-(3-Methylcarbonyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950373)

A mixtureN4-(3-methylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand hydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN4-(3-methylcarbonyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ 11.21 (s, 1H), 10.11 (s, 1H), 9.85(s, 1H), 6.54-8.23 (m, 9H), 4.32 (s, 2H), 2.63 (d, J=7.0 Hz, 3H), 2.47(s, 3H); LCMS: purity: 92.4%; MS (m/e): 425.28 (MH⁺).

7.3.946N4-(3-Phenylcarbonyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950374)

A mixtureN4-(3-phenylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand hydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN4-(3-phenylcarbonyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ 11.63 (s, 1H), 10.30 (s, 1H), 9.85(s, 1H), 6.44-8.43 (m, 14H), 4.42 (s, 2H), 2.63 (d, J=7.0 Hz, 3H); LCMS:purity: 92.4%; MS (m/e): 487.31 (MH⁺).

7.3.947 N2,N4-Bis(3-methylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R950376)

A mixture of 2,4-dichloro-5-fluoropyridine and three equivalents of3-acetophenone in MeOH in a pressure tube at 110° C. for 24 h or in EtOHusing microwave at 175° C. for 10-20 min followed by aqueous work upgave N2,N4-bis(3-methylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine asa white solid. LCMS: purity: 93.1%; MS (m/e): 365.19 (MH⁺).

7.3.948 N2,N4-Bis(3-phenylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R950377)

A mixture of 2,4-dichloro-5-fluoropyridine and three equivalents of3-benzophenone in MeOH in a pressure tube at 110° C. for 24 h or in EtOHusing microwave at 175° C. for 10-20 min followed by aqueous work upgave N2,N4-bis(3-phenylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine asa white solid. LCMS: purity: 95.7%; MS (m/e): 489.29 (MH⁺).

7.3.949N2,N4-Bis(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-2,4-pyrimidinediamine(R950378)

A solution ofN2,N4-bis(4-methoxycarbonylethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediaminein TfOH was heated for 2 hours at 100° C. Aqueous work up followed byflash chromatography on silica gel gaveN2,N4-bis(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ 9.36 (s, 1H), 9.14 (s, 1H), 8.06 (d,1H, J=2.4 Hz), 7.72-7.99 (m, 3H), 6.97 (d, J=7.2 Hz, 1H), 6.87 (d, J=7.2Hz, 1H), 4.42-4.52 (m, 4H), 2.70-2.78 (m, 4H); LCMS: purity: 94.3%; MS(m/e): 484.50 (MH⁺).

7.3.950N2,N4-Bis(3-methylcarbonyloximephenyl)-5-fluoro-2,4-pyrimidinediamine(R950379)

A mixture ofN2,N4-bis(3-methylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine andhydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN2,N4-bis(3-methylcarbonyloximephenyl)-5-fluoro-2,4-pyrimidinediamine asa white solid. ¹H NMR (DMSO): δ 11.21 (s, 1H), 10.11 (s, 1H), 9.85 (s,1H), 6.54-8.23 (m, 9H), 4.32 (s, 2H), 2.63 (d, J=7.0 Hz, 3H), 2.47 (s,3H); LCMS: purity: 92.1%; MS (m/e): 393.06 (M−H⁻).

7.3.951N2,N4-Bis(3-phenylcarbonyloximephenyl)-5-fluoro-2,4-pyrimidinediamine(R950380)

A mixture ofN2,N4-bis(3-phenylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine andhydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN2,N4-bis(3-phenylcarbonyloximephenyl)-5-fluoro-2,4-pyrimidinediamine asa white solid. LCMS: purity: 93.3%; MS (m/e): 486.05 (M−H⁻).

7.3.952N2,N4-Bis(2,3-dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-2,4-pyrimidinediamine(R950381)

A mixture ofN2,N4-bis(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-2,4-pyrimidinediamineand hydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN2,N4-bis(2,3-dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-2,4-pyrimidinediamineas a white solid. LCMS: purity: 98.1%; MS (m/e): 449.03 (M−H⁻).

7.3.953N4-(4-Acetyloxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950382)

A solution ofN4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein pyridine was treated with acetic anhydride at 22° C. for 16 hours.Aqueous work up gaveN4-(4-acetyloxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine as a white solid. ¹H NMR (DMSO): δ10.43 (bs, 1H), 9.62 (bs, 1H), 8.03 (d, 1H, J=2.4 Hz), 7.10-7.83 (m,7H), 6.83 (d, 1H, J=7.4 Hz), 6.52 (d, 1H, J=7.2 Hz), 5.01 (m, 1H), 4.75(s, 2H), 4.03-4.32 (m, 2H), 2.62 (s, 3H), 2.23 (s, 3H), 1.93-2.13 (m,2H); LCMS: purity: 92.1%; MS (m/e): 393.06 (M−H⁻).

7.3.954N4-(4-Azido-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950383)

A solution ofN4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein dry THF was treated with 2 equivalents of DPPA and DBU. The mixturewas stirred for 3 hours at 22° C., concentrated to dryness and purifiedby flash chromatography on silica gel to giveN4-(4-azido-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ 10.09 (bs, 1H), 9.83 (bs, 1H), 8.18(d, 1H, J=2.4 Hz), 7.97 (m, 1H), 7.11-7.61 (m, 6H), 6.82 (d, 1H, J=7.8Hz), 6.62 (d, 1H, J=7.2 Hz), 4.78 (s, 2H), 4.03-4.33 (m, 3H), 2.62 (s,3H), 1.93-2.13 (m, 2H); LCMS: purity: 97.9%; MS (m/e): 463.07 (MH⁺).

7.3.955N4-(4-Benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950385)

A solution ofN4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein THF was treated with bortrifluoride etherate at 80° C. for 8 hours.Aqueous work up gaveN4-(4-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ 9.18 (s, 1H), 9.14 (s, 1H), 8.03 (d,J=2.4 Hz, 1H), 7.93 (bs, 1H), 5.86-7.48 (m, 9H) 4.73-4.74 (m, 2H), 4.33(s, 2H), 2.62 (s, 3H); LCMS: purity: 96.5%; MS (m/e): 420.07 (M−H⁻).

7.3.956N4-(3-Hydroxymethylen-4-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950386)

A mixture of equimolar amounts of2-chloro-N4-(3-hydroxymethylen-4-methoxyphenyl)-5-fluoro-4-aminopyridineand 3-(N-methylamino)carbonylmethylene oxyaniline in MeOH in a pressuretube at 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20min followed by aqueous work up gaveN4-(3-hydroxymethylen-4-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 89.2%; MS (m/e): 410.5 (MH⁺).

7.3.957N4-(3-Amino-4-ethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950388)

A mixture of2-chloro-N4-(3-amino-4-ethoxyphenyl)-5-fluoro-4-aminopyridine and 3equivalents of 3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in apressure tube at 110° C. for 24 h or in EtOH using microwave at 175° C.for 10-20 min followed by aqueous work up gaveN4-(3-amino-4-ethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 95.1%; MS (m/e): 427.18 (MH⁺).

7.3.958N4-(4-Ethoxy-3-hydroxysulfonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950389)

A solution ofN4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein HOAc was treated with sodium nitrate followed by addition ofconcentrated aqueous HCl and copper dichloride. The mixture was stirredfor 2 hours at 22° C. for 8 hours and purified by aqueous work upfollowed by column chromatography on silica gel to giveN4-(4-ethoxy-3-hydroxysulfonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 82.3%; MS (m/e): 474.09 (M−H⁻).

7.3.959N2,N4-Bis(3-methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950391)

A mixture of 2,4-dichloro-5-fluoropyridine and three equivalents of3-methoxycarbonyl-4-trifluoromethoxyaniline in MeOH in a pressure tubeat 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20 minfollowed by aqueous work upN2,N4-bis(3-methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamineas a white solid. ¹HNMR (DMSO): δ 9.96 (s, 1H), 9.82 (s, 1H), 8.16-8.26(m, 4H), 7.91 (dd, 1H, J=3.0, 7.2 Hz), 7.42 (d, 1H, J=7.2 Hz), 7.31 (d,1H, J=7.2 Hz), 3.77 (s, 3H), 3.75 (s, 3H); LCMS: purity: 93.0%; MS(m/e): 565.37 (MH⁺).

7.3.960N4-(3-Methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950392)

A mixture of equimolar amounts of2-chloro-N4-(3-methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-4-aminopyridineand 3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in a pressuretube at 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20min followed by aqueous work up gaveN4-(3-methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 95.8%; MS (m/e): 510.41 (MH⁺).

7.3.961N4-(4-Acetylamino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950393)

A solution ofN4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein dry MeCN was treated with concentrated sulfuric acid. The mixture wasstirred for 3 hours at 22° C., concentrated to dryness and purified byflash chromatography on silica gel to giveN4-(4-acetylamino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ 10.46 (bs, 1H), 9.52 (bs, 1H), 7.98(d, 1H, J=2.4 Hz), 7.12-7.73 (m, 7H), 6.66 (d, 1H, J=7.2 Hz), 6.49 (d,1H, J=7.2 Hz), 4.75 (s, 2H), 4.03-4.32 (m, 2H), 3.80 (m, 1H), 2.64 (s,3H), 2.143 (s, 3H), 1.90-2.11 (m, 2H); LCMS: purity: 92.1%; MS (m/e):393.06 (M−H⁻). LCMS: purity: 96.2%; MS (m/e): 479.13 (M−H⁻).

7.3.962N4-[2,4-Dihydro-1-oxo-4H-imidazo[2,1-c][1,4]benzoxazin-8-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945236)

N4-[2H-1,4-Benzoxazin-3(4H)-one-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (800mg, 2.18 mmol) and phosphorus pentasulfide (800 mg, 1.80 mmol) werestirred in pyridine (5 mL) at 70° C. for 2 h. The reaction solution wastreated with 1N HCl solution to pH 5. The precipitation was collectedwith filtration, washed with water, dried to giveN4-[2H-1,4-benzoxazin-3(4H)-thione-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.

N4-[2H-1,4-Benzoxazin-3(4H)-thione-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(400 mg, 1.04 mmol), glycine (500 mg) and triethylamine (0.5 mL) werestirred in methanol (10 mL) at 70° C. overnight. The undissolved saltwas filtered off, washed with methanol. The filtrate was evaporated andredissolved in THF (5 mL) and DMF (5 mL). To the solution were added EDC(200 mg), HOAt (200 mg) and diisopropylethylamine (0.2 mL). The reactionsolution was stirred at 70° C. for 0.5 h. The mixture was diluted withethyl acetate (60 mL) and washed with water (2×60 mL). The organic layerwas separated, dried, evaporated and purified by flash columnchromatography (EtOAc/hexanes=1:1, EtOAc) to giveN4-[2,4-dihydro-1-oxo-4H-imidazo[2,1-c][1,4]benzoxazin-8-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamineas a white solid. ¹H NMR (CDCl₃): δ 4.35 (t, J=2.1 Hz, 2H), 4.92 (t,J=2.1 Hz, 2H), 6.44 (dd, J=1.5 and 8.1 Hz, 1H), 6.81 (m, 2H), 6.99 (s,1H), 7.11 (m, 2H), 7.39 (m, 2H), 7.97 (d, J=3.0 Hz, 1H), 8.02 (s, 1H),8.57 (d, J=2.4 Hz, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ −167.46; LCMS: ret.time: 13.71 min.; purity: 93.18%; MS (m/e): 407.10 (MH⁺).

7.3.9635-Fluoro-N2-(3-hydroxyphenyl)-N4-[1-oxo-1,2,3,6-tetrahydropyrimido[2,1-c][1,4]benzoxazin-9-yl]-2,4-pyrimidinediamine(R945237)

In a manner analogous to the preparation ofN4-[2,4-dihydro-1-oxo-4H-imidazo[2,1-c][1,4]benzoxazin-8-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-[2H-1,4-benzoxazin-3(4H)-thione-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(400 mg, 1.04 mmol) and β-alanine (500 mg) gave5-fluoro-N2-(3-hydroxyphenyl)-N4-[1-oxo-1,2,3,6-tetrahydropyrimido[2,1-c][1,4]benzoxazin-9-yl]-2,4-pyrimidinediamineas a white solid. 1H NMR (acetone-d₆): δ 2.68 (t, J=7.2 Hz, 2H), 3.71(t, J=7.2 Hz, 2H), 4.62 (t, J=1.2 Hz, 2H), 6.42 (ddd, J=1.2 and 2.4 and7.5 Hz, 1H), 6.98-7.08 (m, 3H), 7.38 (t, J=2.4 Hz, 1H), 7.62 (dd, J=2.4and 8.7 Hz, 1H), 7.96 (d, J=3.3 Hz, 1H), 8.12 (s, 1H), 8.16 (s, 1H),8.52 (d, J=2.7 Hz, 1H), 8.65 (s, 1H); ¹⁹F NMR (282 MHz, acetone-d₆): δ−168.04.

7.3.9645-Fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-7-yl]-2,4-pyrimidinediamine(R945242)

2H-Pyrido[3,2-b]-1,4-oxazin-3(4H)-one (500 mg) was treated with nitricacid (5 mL) and sulfuric acid (5 mL). The reaction mixture was heated to70° C. for 30 min and then poured into ice-water. The solution wasneutralized with sodium bicarbonate to pH 6. The yellow precipitationwas collected by filtration, washed with water and dried to give amixture of nitrated products (regio-isomers).

The mixture of nitrated compounds was reduced under hydrogenolysisconditions using 10% Pd—C in methanol at 40 psi for 30 min. The catalystwas filtered off. The filtrate was evaporated and treated with2,4-dichloro-5-fluoropyrimidine (200 mg) in methanol (5 mL), water (5mL). The reaction mixture was heated at 70° C. overnight, thenevaporated. The residue was reacted with3-methylaminocarbonylmethyleneoxyaniline (300 mg) in methanol (5 mL) andwater (1 mL) at 100° C. overnight. The reaction mixture was diluted with1N HCl solution (60 mL). The brown precipitation was collected byfiltration, washed with water and dried to give5-fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-7-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 2.62 (d, J=4.8 Hz, 3H), 4.33 (s, 2H), 4.63 (s, 2H),6.48 (dd, J=2.4 and 7.5 Hz, 1H), 7.11 (t, J=8.1 Hz, 1H), 7.27 (d, J=7.8Hz, 1H), 7.36 (s, 1H), 7.86 (d, J=2.1 Hz, 1H), 7.97 (m, 1H), 8.12 (d,J=3.6 Hz, 1H), 8.38 (d, J=2.1 Hz, 1H), 9.33 (s, 1H), 9.46 (s, 1H), 11.18(s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −164.49; LCMS: ret. time: 13.16min.; purity: 79.30%; MS (m/e): 440.16 (MH⁺).

7.3.9655-Fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-7-yl]-2,4-pyrimidinediamine(R945263)

2H-Pyrido[3,2-b]-1,4-oxazin-3(4H)-one (1 g, 6.66 mmol) was refluxed withboron hydride methyl sulfide complex (2 mL) in THF (10 mL) for 30 min togive 2H-pyrido[3,2-b]-1,4-oxazine. In a manner analogous to thepreparation of5-fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-7-yl]-2,4-pyrimidinediamine, 2H-pyrido[3,2-b]-1,4-oxazine wasnitrated, reduced and reacted with 2,4-dichloro-5-fluoropyrimidine (400mg) and 3-methylaminocarbonylmethyleneoxyaniline (500 mg) to give5-fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-7-yl]-2,4-pyrimidinediamineas a gray solid. ¹H NMR (CDCl₃): δ 2.91 (d, J=4.8 Hz, 3H), 3.55 (t,J=4.2 Hz, 2H), 4.24 (t, J=4.5 Hz, 2H), 4.49 (s, 2H), 4.90 (br, 1H), 6.51(dd, J=2.7 and 8.1 Hz, 1H), 6.64 (s, 1H), 6.90 (dd, J=2.1 and 8.1 Hz,1H), 7.08 (s, 1H), 7.14 (br, 1H), 7.18 (t, J=8.1 Hz, 1H), 7.28 (d, J=2.1Hz, 1H), 7.51 (t, J=2.1 Hz, 1H), 7.93 (d, J=3.0 Hz, 1H), 7.95 (d, J=2.4Hz, 1H); LCMS: ret. time: 11.91 min.; purity: 100%; MS (m/e): 426.12(MH⁺).

7.3.9665-Fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-6-yl]-2,4-pyrimidinediamine(R921304)

2H-Pyrido[3,2-b]-1,4-oxazin-3(4H)-one (2.5 g) was dissolved in aceticacid (6 mL) and acetic anhydride (30 mL). Fuming nitric acid (3 mL) wasadded dropwise to the reaction solution in ice-bath. The reactionsolution was stirred in ice-bath overnight. Solution was poured intocrashed ice. The light yellow precipitation was collected by filtration,washed with water and dried to give a mixture of nitrated products(regio-isomers). The mixture was crystallized from dichloromethane togive 6-nitro-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (1 g) as a lightyellow solid.

6-Nitro-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (1 g) was reduced underhydrogenolysis conditions using 10% Pd—C in methanol (50 mL) and 1N HClsolution (10 mL) at 50 psi for 2 h. The catalyst was filtered off andwashed with methanol and 1N HCl solution. The filtrate was evaporated togive 6-amino-2H-pyrido[3,2-b]-1,4-oxazin-3 (4H)-one.

In a manner analogous to the preparation of5-fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-7-yl]-2,4-pyrimidinediamine,6-amino-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one was reacted with2,4-dichloro-5-fluoropyrimidine (500 mg) and3-methylaminocarbonylmethyleneoxyaniline (500 mg) to give5-fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-6-yl]-2,4-pyrimidinediamineas a beige solid. ¹H NMR (DMSO-d₆): δ 2.63 (d, J=4.5 Hz, 3H), 4.35 (s,2H), 4.62 (s, 2H), 6.47 (dd, J=1.8 and 8.1 Hz, 1H), 7.10 (t, J=8.1 Hz,1H), 7.25 (d, J=8.1 Hz, 1H), 7.37 (m, 2H), 7.59 (d, J=8.4 Hz, 1H), 7.96(d, J=5.1 Hz, 1H), 8.13 (d, J=3.6 Hz, 1H), 9.26 (s, 1H), 9.29 (s, 1H),11.13 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −163.20; LCMS: ret. time:25.22 min.; purity: 97.55%; MS (m/e): 440.25 (MH⁺).

7.3.9675-Fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-6-yl]-2,4-pyrimidinediamine(R945299)

6-Nitro-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (500 mg) was refluxed withboron hydride methyl sulfide complex (1 mL) in THF (10 mL) for 30 min togive 6-nitro-2H-pyrido[3,2-b]-1,4-oxazine. In a manner analogous to thepreparation of5-fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-7-yl]-2,4-pyrimidinediamine,6-nitro-2H-pyrido[3,2-b]-1,4-oxazine was reduced and reacted with2,4-dichloro-5-fluoropyrimidine (500 mg) and3-methylaminocarbonylmethyleneoxyaniline (500 mg) to give5-fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-6-yl]-2,4-pyrimidinediamineas a gray solid. ¹H NMR (CD₃OD): δ 2.81 (s, 3H), 3.48 (t, J=4.5 Hz, 2H),4.14 (t, J=4.5 Hz, 2H), 4.44 (s, 2H), 6.60 (ddd, J=1.5 and 2.7 and 7.5Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 7.14 (d, J=3.0 Hz, 1H), 7.17 (t, J=7.8Hz, 1H), 7.40 (d, J=8.9 Hz, 1H), 7.42 (t, J=2.1 Hz, 1H), 7.92 (d, J=3.3Hz, 1H); ¹⁹F NMR (282 MHz, CD₃OD): δ −168.20; LCMS: ret. time: 25.49min.; purity: 97.56%; MS (m/e): 426.23 (MH⁺).

7.3.968N4-(1,4-Benzoxazin-3-on-7-yl))-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R908698)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(1,4-benzoxazin-3-on-7-yl)pyrimidineamine and3-aminophenol were reacted to yieldN4-(1,4-Benzoxazin-3-on-7-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.1H (DMSO-d6) 8.2 (d, 1H, J=4 Hz), 7.30 (m, 2H), 7.09 (m, 4H), 6.5 (m,1H), 4.6 (s, 2H) purity 95%; MS (m/e): 368 (MH⁺)

7.3.969N2-(1,4-Benzoxazin-3-on-7-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R908699)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)]pyrimidineamine and7-amino-1,4-benzoxazine-3-one were reacted to yieldN2-(1,4-Benzoxazin-3-on-7-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.1H (DMSO-d6) 8.20 (d, 1H, J=4 Hz), 7.10 (m, 5H), 6.65 (m, 1H), 4.54 (s,2H) purity 95% MS (m/e): 368 (MH⁺)

7.3.970 N4-(1,4-Benzoxazine-3-on-7-yl)-5-fluoro-N2-((N-methylacetamido-2)-3-phenoxy)-2,4-pyrimidinediamine (R908700)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-1,4-benzoxazin-3-on-7-yl)phenylpyrimidineamine and3-(N-methylaminocarbonylmethyleneoxy)aniline were reacted to yieldN4-(1,4-Benzoxazine-3-on-7-yl)-5-fluoro-N2-((N-methylacetamido-2)-3-phenoxy)-2,4-pyrimidinediamine 1H (DMSO-d6) 8.2 (d, 1H,J=4 Hz), 8.00 (m, 1H), 7.19 (m, 1H), 7.09 (m, 3H), 6.55 (m, 1H), 4.64(s, 2H), 4.27 (s, 2H), 3.18 (s, 3H), 2.63 (m, 3H) purity 95% MS(m/e):439 (MH⁺)

7.3.971 N4-(1,4-Benzoxazine-3-on-6-yl)-5-fluoro-N2-[(N-methylacetamido-2)-3-phenoxy)]-2,4-pyrimidinediamine (R908701)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[6-(1,4-benzoxazin-3-onyl)]phenylpyrimidineamineand 3-(N-methylaminocarbonylmethyleneoxy)aniline were reacted to yieldN4-(1,4-Benzoxazine-3-on-6-yl)-5-fluoro-N2-[(N-methylacetamido-2)-3-phenoxy]-2,4-pyrimidinediamine 1H (DMSO-d6) 8.2 (d, 1H,J=4 Hz), 8.00 (m, 1H), 7.13 (m, 3H), 6.95 (m, 1H), 6.55 (m, 1H), 4.64(s, 2H), 4.27 (s, 2H), 3.18 (s, 3H), 2.63 (m, 3H) purity 96% MS (m/e):439 (MH⁺)

7.3.972N4-(1,4-Benzoxazine-3-on-6-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R908702)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(1,4-benzoxazin-3-on-6-yl)phenylpyrimidineamine and3-aminophenol were reacted to yieldN4-(1,4-Benzoxazine-3-on-6-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine1H (DMSO-d6) 8.20 (d, 1H, J=4 Hz), 7.22 (m, 2H), 7.03 (m, 4H), 6.55 (m,1H), 4.64 (s, 2H) purity 98% MS (m/e): 368 (MH⁺)

7.3.9735-Fluoro-N4-(3-hydroxyphenyl)-N2-(N-methyl-1,4-benzoxazine-3-on-6-yl)-2,4-pyrimidinediamine(R908703)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-3-on-6-yl)]phenylpyrimidineamineand 3-(N-methylaminocarbonylmethyleneoxy)aniline were reacted to yield5-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-(N-methyl-1,4-benzoxazin-3-on-6-yl)]pyrimidinediamine1H (DMSO-d6) 8.20 (d, 1H, J=4 Hz), 7.23 (m, 6H), 6.55 (m, 1H), 4.64 (s,2H), 3.18 (s, 3H) purity 96%; MS (m/e): 382 (MH⁺)

7.3.9745-Fluoro-N4-(3-hydroxyphenyl)-N2-(N-methyl-1,4-benzoxazin-7-yl)-2,4-pyrimidinediamine(R908704)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)]phenylpyrimidineamineand 3-(N-methylaminocarbonylmethyleneoxy)aniline were reacted to yield5-Fluoro-N4-(3-hydroxyphenyl)-N2-(N-methyl-1,4-benzoxazin-7-yl)-2,4-pyrimidinediamine1H (DMSO-d6) 8.8.13 (d, 1H, J=4 Hz), 7.13 (m, 3H), 6.72 (m, 3H), 6.59(m, 1H), 4.24 (m, 2H), 4.27 (s, 2H), 3.28 (m, 2H), 2.83 (m, 3H) purity93%; MS (m/e): 367 (MH⁺)

7.3.975 5-Fluoro-N2-[(N-methylacetamido-2)-3-phenoxy]-N4-(N-methyl-1,4-benzoxazin-7-yl)-2,4-pyrimidinediamine(R908705)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)]phenylpyrimidineamineand 3-(N-methylaminocarbonylmethyleneoxy)aniline were reacted to yield5-Fluoro-N2-[(N-methylacetamido-2)-3-phenoxy]-N4-(N-methyl-1,4-benzoxazin-7-yl)-2,4-pyrimidinediamine1H (DMSO-d6) 8.20 (d, 1H, J=4 Hz), 7.13 (m, 5H), 6.75 (m, 2H), 4.44 (s,2H), 4.27 (m, 2H), 3.22 (m, 2H), 2.83 (s, 3H), 2.63 (m, 3H) purity 96%;MS (m/e): 439 (MH⁺)

7.3.976N2-(1,4-Benzoxazin-7-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R908706)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)]pyrimidineamine and7-amino-1,4-benzoxazine were reacted to yieldN2-(1,4-Benzoxazin-7-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.1H (DMSO-d6) 7.95 (d, 1H, J=4 Hz), 7.43 (m, 1H), 7.02 (m, 4H), 6.42 (m,2H), 4.17 (m, 2H), 3.33 (m, 2H) purity 96%; MS (m/e): 353 (MH⁺)]

7.3.9775-Fluoro-N2-(3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-7-yl)-2,4-pyrimidinediamine(R908707)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-7-yl)pyrimidineamine and3-aminophenol were reacted to yield5-Fluoro-N2-(3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-7-yl)-2,4-pyrimidinediamine.1H (DMSO-d6) 8.20 (d, 1H, J=4 Hz), 7.10 (m, 5H), 6.65 (m, 1H), 4.54 (s,2H) purity 95% MS (m/e): 368 (MH⁺)

7.3.978 5-Fluoro-N4-(3-hydroxyphenyl)N2-(N-Methyl-1,4-benzoxazine-3-on-7-yl)-2,4-pyrimidinediamine (R908708)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)pyrimidineamine and7-amino-4-N-methyl-1,4-benzoxazine-3-one were reacted to yield5-Fluoro-N4-(3-hydroxyphenyl)N2-(N-Methyl-1,4-benzoxazine-3-on-7-yl)-2,4-pyrimidinediamine. 1H(DMSO-d6) 8.20 (d, 1H, J=4 Hz), 7.23 (m, 1H), 7.15 (m, 5H), 6.62 (m,1H), 4.64 (s, 2H), 4.27 (s, 2H), 3.18 (s, 3H) purity 95%; MS (m/e): 380(MH⁺)]

7.3.9795-Fluoro-N2-(3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-3-on-6-yl)-2,4-pyrimidinediamine(R908709)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)]pyrimidineamine and6-amino-1,4-benzoxazine were reacted to yield5-Fluoro-N2-(3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-3-on-6-yl)-2,4-pyrimidinediamine.1H (DMSO-d6) 8.20 (d, 1H, J=4 Hz), 7.43 (m, 2H), 7.19 (m, 4H), 6.55 (m,1H), 4.64 (s, 2H), 3.25 (s, 3H) purity 95%; MS (m/e): 382 (MH⁺)

7.3.9805-Fluoro-N2-(3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-6-yl)-2,4-pyrimidinediamine(R908710)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)pyrimidineamine and6-amino-1,4-benzoxazine were reacted to yield5-Fluoro-N2-(3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-6-yl)-2,4-pyrimidinediamine.1H (MeOD-d4) 8.20 (d, 1H, J=4 Hz), 7.43 (m, 3H), 6.90 (m, 2H), 6.75 (m,1H), 4.25 (m, 2H), 3.25 (m, 2H), 2.85 (bs, 1H) purity 96%; MS (m/e): 382(MH⁺)

7.3.981N4-(1,4-Benzoxazin-7-yl)-5-fluoro-N2-(3-hydroxyphenyl)-pyrimidinediamine(R908711)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-[6-(1,4-benzoxazinyl)]-N2-chloro-5-fluoropyrimidineamine and3-ethoxyocarbonylmethyleneoxyaniline were reacted to yieldN4-(1,4-Benzoxazin-7-yl)-5-fluoro-N2-(3-hydroxyphenyl)-pyrimidinediamine¹H NMR (MeOD-d4): δ 8.2 (d, 1H, J=4 Hz), 7.15 (m, 4H), 6.84 (m, 2H),6.62 (m, 1H), 4.65 (s, 2H), 4.15 (m, 4H), 3.28 (m, 2H), 1.19 (t, 3H. J=7Hz) purity 94%; MS (m/e): 439 (MH⁺).

7.3.982 (+/−)-5-Fluoro-N2-[(N-methylacetamido-2)-3-phenoxy]-N4-(2-methyl-1,4-benzoxazin-6-yl)-2,4-pyrimidinediamine(R908712)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,(+/−)-2-chloro-5-fluoro-N4-(2-methyl-1,4-benzoxazin-6-yl)]phenylpyrimidineamineand 3-(N-methylaminocarbonylmethyleneoxy)aniline were reacted to yield(+/−)-5-Fluoro-N2-[(N-methylacetamido-2)-3-phenoxy]-N4-(2-methyl-1,4-benzoxazin-6-yl)-2,4-pyrimidinediamine1H (DMSO-d6) 8.20 (d, 1H, J=4 Hz), 8.13 (m, 1H), 7.1 (m, 5H), 6.96 (m,1H), 6.63 (m, 1H), 4.62 (m, 1H), 4.40 (s, 3H), 2.63 (m, 3H), 1.25 (m,3H) purity 93%; MS (m/e): 453 (MH⁺)

7.3.983N2-(N-Ethylcarbonylmethyleneoxy-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-hydroxyphenyl)phenyl]pyrimidinediamine(R908734)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-Chloro-5-fluoro-N4-(3-hydroxyphenyl)pyrimidineamine and6-Amino-N-carbomethoxy-1,4-benzoxazine were reacted to yieldN2-(N-Ethylcarbonylmethyleneoxy-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-hydroxyphenyl)phenyl]pyrimidinediamine¹H NMR (DMSO-d6): δ 8.23 (m, 1H), 7.20 (m, 1H), 7.14 (m, 4H), 6.95 (m,1H), 6.76 (m, 1H), 4.66 (s, 1H), 4.48 (s, 1H), 4.25 (q, 2H J=6.5 Hz),1.28 (t, 2H, J=6.5 Hz), purity 95% MS (m/e): 454 (MH⁺).

7.3.984N4-(1,4-Benzoxazin-6-yl)-N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoropyrimidinediamine(R909255)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-[6-(1,4-benzoxazinyl)]-N2-chloro-5-fluoropyrimidineamine and3-chloro-4-hydroxy-5-methylaniline were reacted to yieldN4-(1,4-benzoxazin-6-yl)-N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoropyrimidinediamine¹H NMR (DMSO-d6): δ 7.89 (d, 1H, J=4 Hz), 7.25 (m, 1H), 7.14 (m, 1H),6.80 (m, 2H), 6.82 (m, 1H), 4.29 (s, 2H), 3.35 (m, 2H), 2.20 (s, 3H)purity 99%; MS (m/e): 402 (MH⁺).

7.3.9855-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-(N-methyl-1,4-benzoxazin-6-yl)pyrimidinediamine(R909259)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[6-(N-methyl-1,4-benzoxazinyl)]phenylpyrimidineamine and 3-(N-methylaminocarbonylmethyleneoxy)aniline werereacted to yield5-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-(N-methyl-1,4-benzoxazin-6-yl)pyrimidinediamine1H (DMSO-d6) 8.01 (d, 1H, J=4 Hz), 7.33 (m, 2H), 7.22 (m, 1H), 7.02 (m,2H), 6.65 (m, 1H), 6.42 (m, 1H), 4.37 (s, 2H), 4.22 (m, 2H), 3.18 (m,2H), 2.78 (s, 3H) 2.63 (m, 3H) purity 98%; MS (m/e): 439 (MH⁺)

7.3.986 5-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-[6-(N-methyl-1,4-benzoxazin-3-onyl)]pyrimidinediamine(R909260)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[6-(N-methyl-1,4-benzoxazin-3-onyl)]phenylpyrimidineamineand 3-(N-methylaminocarbonylmethyleneoxy)aniline were reacted to yield5-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-[6-(N-methyl-1,4-benzoxazin-3-onyl)]pyrimidinediamine1H (DMSO-d6) 8.01 (d, 1H, J=4 Hz), 7.33 (m, 2H), 7.22 (m, 1H), 7.02 (m,2H), 6.65 (m, 1H), 6.42 (m, 1H), 4.37 (s, 2H), 4.22 (s, 2H), 3.18 (s,3H), 2.78 (s, 3H) 2.63 (m, 3H) purity 88%; MS (m/e): 453 (MH⁺)

7.3.987 5-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)]-2,4-pyrimidinediamine(R909261)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)phenylpyrimidineamineand 3-(N-methylaminocarbonylmethyleneoxy)aniline were reacted to yield5-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)pyrimidinediamine1H (DMSO-d6) 8.08 (d, 1H, J=4 Hz), 7.43 (m, 2H), 7.19 (m, 1H), 7.09 (m,3H), 6.55 (m, 1H), 4.64 (s, 2H), 4.27 (s, 2H), 3.18 (s, 3H), 2.63 (m,3H) MS (m/e): 453 (MH⁺)

7.3.988(+/−)-5-Fluoro-N4-(3-hydroxyphenyl]-N2-(2-methyl-1,4-benzothiazin-3-on-6-yl)pyrimidinediamine(R909263)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)pyrimidineamine and6-amino-2-methyl-1,4-benzothiazin-3-one were reacted to yield(+/−)-5-Fluoro-N4-(3-hydroxyphenyl]-N2-(2-methyl-1,4-benzothiazin-3-on-6-yl)pyrimidinediamine¹H NMR (MeOD-d4): δ −8.02 (d, 1H, J=4 Hz), 7.30 (m, 3H), 7.08 (m, 3H),6.52 (m, 1H), 3.57 (m, 1H), 1.25 (m, 3H) purity 92%; MS (m/e): 398(MH⁺).

7.3.9895-Fluoro-N2-[3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)-2,4-pyrimidinediamine(R909264)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)]phenylpyrimidineamineand 3-aminophenol were reacted to yield5-Fluoro-N2-[3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)]-2,4-pyrimidinediamine1H (DMSO-d6) 8.08 (d, 1H, J=4 Hz), 7.53 (m, 2H), 7.09 (m, 4H), 6.42 (m,1H), 4.64 (s, 2H), 3.27 (s, 3H) purity 95% MS (m/e): 382 (MH⁺)

7.3.990N4-(3-Ethylcarboxy-4H-imidazo[5,1-c]-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]pyrimidinediamine (R909265)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N2-Chloro-N4-(3-ethylcarboxy-4H-imidazo[5,1-c]-1,4-benzoxazin-6-yl)-5-fluoropyrimidineamineand 3-(N-methylaminocarbonylmethyleneoxy)aniline were reacted to yieldN4-(3-Ethylcarboxy-4H-imidazo[5,1-c]-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]pyrimidinediamine¹H NMR (DMSO-d6): δ 8.23 (m, 2H), 8.08 (d, J=4 Hz, 1H), 7.92 (m, 1H),7.43 (m, 1H), 7.38 (m, 2H), 7.18 (m, 1H), 6.99 (t, 1H), 6.41 (m, 1H),5.43 (s, 2H) purity 92%; MS (m/e): 534 (MH⁺).

7.3.991N4-(1,4-Benzoxazin-7-yl)-N2-[3-ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(R909266)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-(1,4-Benzoxazin-7-yl)-2-chloro-5-fluoro-pyrimidineamine and3-(ethoxycarbonylmethyleneoxy)aniline were reacted to yieldN4-(1,4-Benzoxazin-7-yl)-N2-[3-ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine.1H (DMSO-d6) 8.2 (d, 1H, J=4 Hz), 7.43 (m, 1H), 7.12 (m, 4H), 6.68 (m,2H), 4.7 (s, 2H) 4.17 (m, 2H), 3.33 (m, 2H), 3.13 (m, 2H) 1.87 (m, 3H)purity 89%; MS (m/e): 439 (MH⁺)

7.3.992N2-(3-Ethylcarboxy-4H-imidazo[5,1-c]-1,4-benzoxazin-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)pyrimidinediamine(R909267)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-Chloro-5-fluoro-N4-(3-hydroxyphenyl)pyrimidineamine and 3 Ethyl6-Amino-(3-carboxy-4H-imidazo[5,1-c]-1,4-benzoxazine were reacted toyieldN2-(3-Ethylcarboxy-4H-imidazo[5,1-c]-1,4-benzoxazin-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)pyrimidinediamine¹H NMR (DMSO-d6): δ 8.18 (m, 1H), 8.04 (m, 1H), 7.38 (m, 1H), 7.22 (m,1H), 7.04 (m, 2H), 6.96 (m, 1H), 6.53 (m, 1H), 5.42 (s, 2H), 4.25 (q, 2HJ=6.5 Hz), 1.28 (t, 2H, J=6.5 Hz), purity 92% MS (m/e): 409 (MH⁺).

7.3.993N2-(1,4-Benzoxazin-3-on-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R909268)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamineN4-[6-(1,4-benzoxazinyl)]-N2-chloro-5-fluoropyrimidineamine and6-amino-1,4-benzoxazin-3-one were reacted to yieldN2-(1,4-benzoxazin-3-on-6-yl)-5-fluoro-N4-(6-(1,4-benzoxazinyl)]-)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 8.18 (d, 1H J=4 Hz), 7.17 (m, 2H), 6.88 (m, 2H),6.80 (m, 1H), 6.58 (m, 1H) 4.52 (s, 2H), 4.11 (m, 2H), 3.33 (m, 2H)purity: 97%; MS (m/e): 409 (MH⁺).

7.3.994 N2-[3-(N,N-Dimethylaminocarbonylmethyleneoxy)phenyl]-N4-(1,4-benzoxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R909290)

In like manner toN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)-N2-(3-ethoxyocarbonylmethyleneoxyphenyl)-5-fluoro-pyrimidinediamineand dimethylamine hydrochloride were reacted to yieldN2-[3-(N,N-Dimethylaminocarbonylmethyleneoxy)phenyl]-N4-(1,4-benzoxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine¹H NMR (CD₃OD): δ 7.8 (d, 1H), 7.4 (m, 1H), 7.05 (m, 2H), 7.0 (s, 1H),6.8 (dd, 1H), 6.66 (d, 1H), 6.56 (dd, 1H), 4.35 (s, 2H), 4.18 (m, 2H),3.25 (m, 2H), 2.8 (s, 6H); purity: 95%; MS (m/e): 439 (MH⁺)

7.3.995N4-(4N-Carboxamidino-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R909292)

To a solution in 2 mL THF at 0° Celsius containing 250 mg (0.59 mmol) ofN4-(1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,1.4 eq, 115 uL TEA, and catalytic DMAP was added 0.4 eq,70 mg oftriphosgene. After 30 min 15 mL of aqueous ammonia and stirred for 30min at RT. The THF was evaporated and the reaction was diluted withwater, and the resulting precipitate collection by suction filtration.The crude precipitate was purified by preparative TLC (5% MeOH/EtOAc) toyieldN4-(4N-Carboxamidino-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.83 (m, 1H), 7.42 (m, 1H), 7.12 (m, 2H), 7.08 (s,1H), 6.84 (m, 1H), 6.66 (m, 1H), 6.48 (m, 1H), 4.30 (s, 2H), 4.15 (m,2H), 3.22 (m, 2H), 2.82 (s, 3H); purity: 87%; MS (m/e): 468 (MH⁺).

7.3.996N4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-N2-[3-ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(R909308)

In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N2-Chloro-N4-(3,3-dimethyl-1,4-benzoxazin-6-yl)-5-fluoro-pyrimidineamineand 3-(ethoxycarbonylmethyleneoxy)aniline were reacted to yieldN4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-N2-[3-ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine.1H (DMSO-d6) 8.00 (m, 1H), 7.43 (m, 2H), 7.05 (m, 1H), 6.82 (m, 2H),6.68 (m, 1H), 6.41 (m, 1H), 4.80 (s, 2H), 4.18 (q, 2H), 3.74 (s, 2H),1.03 (t, 3H), 1.00 (s, 6H) purity 99%; MS (m/e): 467 (MH⁺)

7.3.997N4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R909309)

In like manner toN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-N2-[3-ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yieldN4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine. 1H (DMSO-d6) 8.04 (d, 1H),7.93 (m, 1H), 7.45 (m, 2H), 7.09 (m, 1H), 6.93 (m, 2H), 6.62 (m, 1H),6.43 (m, 1H), 4.37 (s, 2H), 3.74 (s, 2H), 2.62 (d, 3H), 1.07 (s, 6H)purity 99%; MS (m/e): 453 (MH⁺)

7.3.998N4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R909309)

In like manner toN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-N2-[3-ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yieldN4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine. 1H (DMSO-d6) 8.04 (d, 1H),7.93 (m, 1H), 7.45 (m, 2H), 7.09 (m, 1H), 6.93 (m, 2H), 6.62 (m, 1H),6.43 (m, 1H), 4.37 (s, 2H), 3.74 (s, 2H), 2.62 (d, 3H), 1.07 (s, 6H)purity 99%; MS (m/e): 453 (MH⁺)

7.3.999N4-(2,4-Diiodo-3-hydroxypheny)-5-fluoro-N2-(3-iodo-1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine(R935221)

To5-fluoro-N2-(3-hydroxyphenyl)-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine(34.4 mg, 0.098 mmole) in ethanol (2.0 mL) and aq. NH₄OH (2.0 mL), I₂(0.126 g, 0.99 mmole atom) was added and stirred at room temperatureovernight. Reaction mixture was concentrated, dissolved in EtOAc andtreated with aq. hypo solution. Organic layer was separated, dried withanhydrous Na₂SO₄ and concentrated. The crude material was purified bysilica gel column chromatography to provideN4-(2,4-diiodo-3-hydroxypheny)-5-fluoro-N2-[3-iodo-1-methyl-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.86 (s, 1H), 9.51 (s, 1H), 9.12 (s, 1H), 8.28 (s,1H), 8.07 (d, 1H, J=3.5 Hz), 7.79 (s, 1H), 7.63 (s, 1H), 7.32 (d, 1H,J=8.8 Hz), 7.37 (d, 1H, J=8.8 Hz), 3.92 (s, 3H). LCMS: ret. time: 20.88min.; purity: 91%; MS (m/e): 729 (MH⁺).

7.3.10005-Fluoro-N4-(4-isopropoxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine(R935222)

In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-isopropoxyphenyl)-4-pyrimidineamine was reactedwith 5-amino-1-(methoxycarbonyl)methylindazoline to provide5-fluoro-N4-(4-isopropoxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.17 (s, 1H), 9.13 (s, 1H), 8.10 (s, 1H), 8.03 (d,1H, J=4.1 Hz), 7.85 (s, 1H), 7.58 (d, 2H, J=8.8 Hz), 7.46 (s, 2H), 6.87(s, 2H, J=8.8 Hz), 5.31 (s, 2H), 4.57 (sep, 1H, J=5.8 Hz), 3.65 (s, 3H),1.25 (d, 6H, J=5.8 Hz). LCMS: ret. time: 21.33 min.; purity: 96%; MS(m/e): 451 (MH⁺).

7.3.1001 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine(R935223)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine wasreacted with 5-amino-1-(methoxycarbonyl)methyl-indazoline to provideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.16 (s, 1H), 9.14 (s, 1H), 8.13 (s, 1H), 8.04 (d,1H, J=4.1 Hz), 7.89 (s, 1H), 7.48 (s, 2H), 7.30 (d, 1H, J=2.9 Hz), 7.20(dd, 1H, J=2.9 and 8.8 Hz), 6.79 (d, 1H, J=8.8 Hz), 5.32 (s, 2H), 4.22(s, 4H), 3.65 (s, 3H). LCMS: ret. time: 21.33 min.; purity: 96%; MS(m/e): 451 (MH⁺).

7.3.10025-Fluoro-N2-(4-isopropoxyphenyl)-N4-[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine(R935224)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N2-(4-isopropoxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provide5-fluoro-N2-(4-isopropoxyphenyl)-N4-[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.46 (s, 1H), 8.98 (s, 1H), 8.07 (d, 1H, J=4.1 Hz),8.02 (d, 1H, J=4.7 Hz), 7.98 (s, 2H), 7.66 (d, 1H, J=8.8 Hz), 7.50 (d,2H, J=8.8 Hz), 7.46 (app s, 1H), 6.74 (d, 2H, J=8.8 Hz), 4.96 (s, 2H),4.46 (sept, 1H, J=5.8 Hz), 2.58 (d, 3H, J=4.7 Hz), 1.21 (d, 6H, J=5.8Hz). LCMS: ret. time: 18.22 min.; purity: 93%; MS (m/e): 450 (MH⁺).

7.3.1003 N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine(R935225)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2-(3,4-ethyelnedioxyphenyl)-5-fluoro-N2-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provide N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.47 (s, 1H), 8.99 (s, 1H), 8.08 (d, 1H, J=3.5 Hz),8.06 (s, 1H), 8.01 (d, 1H, J=4.7 Hz), 7.98 (d, 1H, J=1.1 Hz), 7.66 (d,1H, J=8.8 Hz), 7.45 (dd, 1H, J=1.1 and 8.8 Hz), 7.31 (d, 1H, J=2.3 Hz),7.01 (dd, 1H, J=2.9 and 8.8 Hz), 6.66 (d, 1H, J=8.8 Hz), 4.95 (s, 2H),4.14 (s, 4H), 2.57 (d, 3H, J=4.1 Hz). LCMS: ret. time: 15.55 min.;purity: 94%; MS (m/e): 450 (MH⁺).

7.3.10045-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine(R935237)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with5-amino-1-(methoxycarbonyl)methyl-indazoline to produce5-fluoro-N4-(3-hydroxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.40 (s, 1H), 9.19 (s, 1H), 9.17 (s, 1H), 8.23 (s,1H), 8.07 (d, 1H, J=3.5 Hz), 7.90 (s, 1H), 7.47 (s, 2H), 7.25 (d, 1H,J=7.6 Hz), 7.11 (d, 1H, J=7.6 Hz), 7.08 (d, 1H, J=8.2 Hz), 6.53 (d, 1H,J=8.2 Hz), 5.31 (s, 2H), 3.64 (s, 3H). LCMS: ret. time: 15.82 min.;purity: 96%; MS (m/e): 409 (MH⁺).

7.3.1005 N2,N4-Bis[1-(2-hydroxyethyl)indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamine(R935238)

In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2,N4-bis[1-(methoxycarbonyl)methyl-indazoline-6-yl]-5-fluoro-2,4-pyrimidinediaminewas reacted with DIBAL-H to produce N2,N4-bis[1-(2-hydroxyethyl)indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.56 (s, 1H), 9.43 (s, 1H), 8.19 (d, 1H, J=3.5 Hz),8.06 (s, 1H), 8.03 (s, 1H), 7.98 (s, 1H), 7.86 (s, 1H), 7.66 (d, 1H,J=8.8 Hz), 7.52 (d, 1H, J=8.8 Hz), 7.42 (dd, 1H, J=1.7 and 8.8 Hz), 7.23(dd, 1H, J=1.7 and 8.8 Hz), 4.75 (t, 1H, J=5.3 Hz), 4.68 (t, 1H, J=5.3Hz), 4.09-4.02 (m, 2H), 3.81-3.74 (m, 2H), 3.63-3.60 (m, 2H), 3.56-3.52(m, 2H). LCMS: ret. time: 13.73 min.; purity: 90%; MS (m/e): 449 (MH⁺).

7.3.10065-Fluoro-N4-(4-isopropoxyphenyl)-N2-[1-(N-methylaminocarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine(R935239)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(4-isopropoxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provide5-fluoro-N4-(4-isopropoxyphenyl)-N2-[1-(N-methylaminocarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.27 (s, 1H), 9.21 (s, 1H), 8.07 (s, 1H), 8.04 (d,1H, J=4.1 Hz), 7.90 (qt, 1H, J=4.7 Hz), 7.83 (s, 1H), 7.58 (d, 2H, J=8.8Hz), 7.44 (s, 2H), 6.87 (d, 2H, J=8.8 Hz), 4.98 (s, 2H), 4.57 (q, 1H,J=5.8 Hz), 2.59 (d, 3H, J=4.1 Hz), 1.21 (d, 6H, J=5.8 Hz). LCMS: ret.time: 17.74 min.; purity: 94%; MS (m/e): 450 (MH⁺).

7.3.1007 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(N-methylaminocarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine(R935240)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(N-methylaminocarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.36 (br s, 2H), 8.06 (d, 1H, J=3.5 Hz), 8.05 (s,1H), 7.99 (qt, 1H, J=4.7 Hz), 7.87 (s, 1H), 7.46 (s, 2H), 7.30-7.28 (m,1H), 7.20-7.17 (m, 1H), 6.79 (d, 1H, J=8.8 Hz), 4.99 (s, 2H), 4.22 (s,4H), 2.59 (d, 3H, J=4.7 Hz). LCMS: ret. time: 15.06 min.; purity: 91%;MS (m/e): 450 (MH⁺).

7.3.10085-Fluoro-N2-(4-isopropoxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine(R935242)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-4-pyrimidineaminewas reacted with 4-isopropoxyaniline to provide5-fluoro-N2-(4-isopropoxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.58 (s, 1H), 10.09 (s, 1H), 8.23 (d, 1H, J=5.3Hz), 8.04 (s, 1H), 8.02 (s, 1H, J=5.8 Hz), 7.68-7.63 (m 1H), 7.58-7.55(s, 1H), 7.30 (d, 2H, J=8.8 Hz), 6.82 (d, 2H, J=8.8 Hz), 5.41 (s, 2H),4.53 (sept, 1H, J=5.8 Hz), 3.66 (s, 3H), 1.21 (d, 6H, J=5.8 Hz). LCMS:ret. time: 19.30 min.; purity: 93%; MS (m/e): 451 (MH⁺).

7.3.1009 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(2-hydroxyethyl)indazoline-6-yl]-2,4-pyrimidinediamine(R935248)

In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediaminewas reacted with DIBAL-H to produce N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(2-hydroxyethyl)indazoline-6-yl]-2,4-pyrimidinediamine.LCMS: ret. time: 19.42 min.; purity: 94%; MS (m/e): 423 (MH⁺).

7.3.1010 N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine(R935249)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-4-pyridinaminewas reacted with 3, 4-ethylenedioxyaniline to provide N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.32 (s, 1H), 8.94 (s, 1H), 8.14 (d, 1H, J=4.7 Hz),8.03 (d, 1H, J=4.7 Hz), 8.01 (s, 1H), 7.65-7.57 (m, 2H), 7.23 (d, 1H,J=1.7 Hz), 7.02 (dd, 1H, J=1.9 and 8.8 Hz), 6.63 (d, 1H, J=8.8 Hz), 5.38(s, 2H), 4.14 (s, 4H), 3.66 (s, 3H). LCMS: ret. time: 18.94 min.;purity: 91%; MS (m/e): 451 (MH⁺).

7.3.10115-Fluoro-N2-(3-hydroxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine(R935250)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-4-pyrimidineaminewas reacted with 3-aminophenol to provide5-fluoro-N2-(3-hydroxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.34 (s, 1H), 9.16 (s, 1H), 8.25 (d, 1H, J=4.7 Hz),8.05 (d, 1H, J=4.7 Hz), 8.02 (s, 1H), 7.65-7.57 (m, 2H), 7.10 (d, 2H,J=5.8 Hz), 6.93 (d, 1H, J=8.8 Hz), 6.90 (d, 1H, J=8.8 Hz), 6.28 (app d,1H, J=8.8 Hz), 5.37 (s, 2H), 3.66 (s, 3H). LCMS: ret. time: 17.87 min.;purity: 97%; MS (m/e): 409 (MH⁺).

7.3.10125-Fluoro-N4-(4-isopropoxyphenyl)-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine(R935251)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-isopropoxyphenyl)-4-pyrimidineamine was reactedwith 1-aminopyrrole to provide5-fluoro-N4-(4-isopropoxyphenyl)-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.93 (s, 1H), 9.21 (s, 1H), 7.97 (d, 1H, J=4.1 Hz),7.47 (d, 2H, J=8.8 Hz), 6.70 (dd, 2H, J=2.3 and 4.7 Hz), 6.67 (d, 2H,J=8.8 Hz), 6.02 (dd, 2H, J=2.3 and 4.7 Hz), 4.48 (sept, 1H, J=5.8 Hz),1.21 (d, 6H, J=5.8 Hz). LCMS: ret. time: 23.44 min.; purity: 90%; MS(m/e): 328 (MH⁺).

7.3.1013 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine(R935252)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine wasreacted with 1-aminopyrrole to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.95 (s, 1H), 9.16 (s, 1H), 7.95 (d, 1H, J=3.5 Hz),7.16-7.12 (m, 2H), 6.69 (dd, 2H, J=2.3 and 4.7 Hz), 6.61 (d, 1H, J=8.8Hz), 5.99 (dd, 2H, J=2.3 and 4.7 Hz), 4.12-4.15 (m, 4H). LCMS: ret.time: 19.86 min.; purity: 92%; MS (m/e): 328 (MH⁺).

7.3.10145-Fluoro-N4-(3-hydroxyphenyl)-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine(R935253)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with1-aminopyrrole to provide5-fluoro-N4-(3-hydroxyphenyl)-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.95 (s, 1H), 9.22 (s, 1H), 9.19 (s, 1H), 7.99 (d,1H, J=3.5 Hz), 7.22 (d, 1H, J=8.2 Hz), 6.94 (br s, 1H), 6.89 (t, 1H,J=8.2 Hz), 6.70 (dd, 2H, J=2.3 and 4.7 Hz), 6.38 (d, 1H, J=8.2 Hz), 5.99(t, 2H, J=2.3 and 4.7 Hz). LCMS: ret. time: 18.23 min.; purity: 94%; MS(m/e): 286 (MH⁺).

7.3.10155-Fluoro-N2-[1-(2-hydroxyethyl)indazoline-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine(R935255)

In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(4-isopropoxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediaminewas reacted with DIBAL-H to produce5-fluoro-N2-[1-(2-hydroxyethyl)indazoline-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.16 (s, 1H), 9.10 (s, 1H), 8.09 (s, 1H), 8.02 (s,1H, J=4.0 Hz), 7.79 (s, 1H), 7.59 (d, 2H, J=8.8 Hz), 7.48 (d, 1H, J=8.8Hz), 7.42 (dd, 1H, J=1.7 and 8.8 Hz), 6.87 (d, 2H, J=8.8 Hz), 4.83 (t,1H, J=5.8 Hz), 4.57 (sept, 1H, J=5.8 Hz), 4.35 (t, 2H, J=5.8 Hz), 3.75(app qt, 2H, J=5.8 Hz), 1.26 (d, 6H, J=5.8 Hz). LCMS: ret. time: 20.90min.; purity: 94%; MS (m/e): 423 (MH⁺).

7.3.10165-Fluoro-N2-[1-(2-hydroxyethyl)indazoline-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R935256)

In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-hydroxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediaminewas reacted with DIBAL-H to produce5-fluoro-N2-[1-(2-hydroxyethyl)indazoline-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.39 (s, 1H), 9.18 (s, 1H), 9.14 (s, 1H), 8.19 (s,1H), 8.07 (d, 1H, J=4.1 Hz), 7.84 (s, 1H), 7.50-7.42 (m, 2H), 7.26 (d,1H, J=8.2 Hz), 7.12-7.06 (m, 2H), 6.52 (d, 1H, J=8.2 Hz), 4.83 (t, 1H,J=5.8 Hz), 4.35 (t, 2H, J=5.8 Hz), 3.75 (app qt, 2H, J=5.8 Hz). LCMS:ret. time: 15.97 min.; purity: 95%; MS (m/e): 381 (MH⁺).

7.3.1017 N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-(2-hydroxyethyl)indazoline-5-yl]-2,4-pyrimidinediamine(R935258)

In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediaminewas reacted with DIBAL-H to produce N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[1-(2-hydroxyethyl)indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.20 (s, 1H), 8.93 (s, 1H), 8.12 (s, 1H), 8.02 (d,1H, J=3.5 Hz), 7.94 (s, 1H), 7.59 (s, 2H), 7.23 (d, 1H, J=0.9 Hz), 7.02(dd, 1H, J=1.0 and 8.8 Hz), 6.64 (d, 1H, J=8.8 Hz), 4.86 (t, 1H, J=5.3Hz), 4.40 (t, 2H, J=5.8 Hz), 4.15 (s, 4H), 3.78 (app qt, 2H, J=5.3 and5.8 Hz). LCMS: ret. time: 18.07 min.; purity: 93%; MS (m/e): 423 (MH⁺).

7.3.10185-Fluoro-N4-[1-(2-hydroxyethyl)indazoline-5-yl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R935259)

In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,5-fluoro-N2-(3-hydroxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediaminewas reacted with DIBAL-H to produce5-fluoro-N4-[1-(2-hydroxyethyl)indazoline-5-yl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.31 (s, 1H), 9.16 (s, 1H), 9.01 (s, 1H), 8.23 (s,1H), 8.05 (d, 1H, J=3.5 Hz), 7.96 (s, 1H), 7.60 (s, 2H), 7.10 (app s,2H), 6.92 (t, 1H, J=8.8 Hz), 6.31 (d, 1H, J=8.8 Hz), 4.86 (t, 1H, J=5.3Hz), 4.40 (t, 2H, J=5.8 Hz), 3.79 (app qt, 2H, J=5.3 and 5.8 Hz). LCMS:ret. time: 16.09 min.; purity: 89%; MS (m/e): 381 (MH⁺).

7.3.1019 N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-(indazoline-6-yl)-2,4-pyrimidinediamine(R935261)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(indazoline-6-yl)-4-pyrimidineamine was reacted 3,4-ethyelenedioxyaniline to produce N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-(indazoline-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 12.85 (s, 1H), 9.40 (s, 1H), 9.01 (s, 1H), 8.07 (d,1H, J=3.5 Hz), 7.97 (s, 1H), 7.86 (s, 1H), 7.65 (d, 1H, J=8.8 Hz), 7.47(dd, 1H, J=2.3 and 8.8 Hz), 7.27 (d, 1H, J=2.3 Hz), 7.07 (dd, 1H, J=2.3and 8.8 Hz), 6.64 (dd, 1H, J=1.7 and 8.8 Hz), 4.14 (s, 4H). LCMS: ret.time: 15.90 min.; purity: 100%; MS (m/e): 379 (MH⁺).

7.3.10205-Fluoro-N2-(3-hydroxyphenyl)-N4-(indazoline-6-yl)-2,4-pyrimidinediamine(R935262)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(indazoline-6-yl)-4-pyrimidineamine was reacted with3-aminophenol to produce5-fluoro-N2-(3-hydroxyphenyl)-N4-(indazoline-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.80 (s, 1H), 10.49 (s, 1H), 8.35 (d, 1H, J=5.3Hz), 8.06 (s, 1H), 7.78 (d, 1H), 7.75 (d, 1H, J=8.8 Hz), 7.42 (dd, 1H,J=1.7 and 8.8 Hz), 6.99-6.97 (m, 2H), 6.80 (s, 1H), 6.52-6.48 (m, 1H).LCMS: ret. time: 13.78 min.; purity: 100%; MS (m/e): 379 (MH⁺).

7.3.1021N2-(3-Chloro-4-hydroxy-3-methylphenyl)-5-fluoro-N4-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-2,4-pyrimidinediamine(R935263)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-4-pyrimidineaminewas reacted with 4-amino-2-chloro-6-methylphenol to produceN2-(3-chloro-4-hydroxy-3-methylphenyl)-5-fluoro-N4-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.40 (s, 1H), 9.04 (s, 1H), 8.51 (s, 1H), 8.07 (d,1H, J=3.5 Hz), 7.98 (d, 1H, J=2.3 Hz), 7.67 (s, 1H), 7.53 (s, 1H),7.41-7.36 (m, 1H), 7.20 (s, 1H), 7.10 (d, 1H, J=8.8 Hz), 7.07 (s, 1H),5.24 (s, 2H), 1.98 (s, 3H). LCMS: ret. time: 13.36 min.; purity: 90%; MS(m/e): 439 (MH⁺).

7.3.1022N2-(3-Chloro-4-hydroxy-3-methylphenyl)-5-fluoro-N4-(indazoline-6-yl)-2,4-pyrimidinediamine(R935264)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(indazoline-6-yl)-4-pyrimidineamine was reacted with4-amino-2-chloro-6-methylphenol to produceN2-(3-chloro-4-hydroxy-3-methylphenyl)-5-fluoro-N4-(indazoline-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.62 (s, 1H), 9.19 (s, 1H), 8.61 (s, 1H), 8.12 (s,1H), 8.02 (s, 1H), 7.77 (s, 1H), 7.67 (d, 1H, J=8.8 Hz), 7.50-7.45 (m,2H), 7.26 (s, 1H), 1.98 (s, 3H). LCMS: ret. time: 13.78 min.; purity:100%; MS (m/e): 385 (MH⁺).

7.3.10235-Fluoro-N4-(indazoline-5-yl)-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine(R935266)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(indazoline-5-yl)-4-pyrimidineamine was reacted with4-isoporopoxyaniline to produce5-fluoro-N4-(indazoline-5-yl)-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.30 (s, 1H), 9.80 (s, 1H), 8.16 (d, 1H, J=5.3 Hz),8.06 (s, 1H), 7.98 (s, 1H), 7.51 (s, 2H), 7.32 (d, 2H, J=8.8 Hz), 6.79(d, 2H, J=8.8 Hz), 4.51 (sept, 1H, J=5.8 Hz), 1.22 (d, 6H, J=5.8 Hz).LCMS: ret. time: 17.65 min.; purity: 98%; MS (m/e): 379 (MH⁺).

7.3.1024 N2-(3,4-Ethyelenedioxyphenyl)-5-fluoro-N4-(indazoline-5-yl)-2,4-pyrimidinediamine(R935267)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(indazoline-5-yl)-4-pyrimidineamine was reacted with3, 4-ethylenedioxyphenylaniline to produce N2-(3,4-ethyelenedioxyphenyl)-5-fluoro-N4-(indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.20 (s, 1H), 9.61 (s, 1H), 8.13 (d, 1H, J=5.3 Hz),8.08 (s, 1H), 7.98 (s, 1H), 7.54-7.48 (m, 2H), 7.06 (d, 1H, J=2.3 Hz),6.90 (dd, 1H, J=2.3 and 8.8 Hz), 6.72 (d, 1H, J=8.8 Hz), 4.17 (s, 4H).LCMS: ret. time: 15.16 min.; purity: 100%; MS (m/e): 379 (MH⁺).

7.3.10255-Fluoro-N2-(3-hydroxyphenyl)-N4-(indazoline-5-yl)-2,4-pyrimidinediamine(R935268)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(indazoline-5-yl)-4-pyrimidineamine was reacted with3-aminophenol to produce5-fluoro-N2-(3-hydroxyphenyl)-N4-(indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.64 (s, 1H), 10.33 (s, 1H), 8.29 (d, 1H, J=5.3Hz), 8.12 (s, 1H), 8.03 (s, 1H), 7.55 (dd, 2H, J=1.7 and 8.8 Hz), 7.00(d, 1H, J=8.8 Hz), 6.90 (d, 1H, J=8.8 Hz), 6.85 (d, 1H, J=1.7 Hz), 6.53(d, 1H, J=8.8 Hz). LCMS: ret. time: 12.80 min.; purity: 98%; MS (m/e):337 (MH⁺).

7.3.1026 5-Fluoro-N4-(indazoline-5-yl)-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine (R935269)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(indazoline-5-yl)-4-pyrimidineamine was reacted with3-(methoxycarbonylmethyleneoxy)aniline to produce5-fluoro-N4-(indazoline-5-yl)-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.64 (s, 1H), 9.82 (s, 1H), 8.20 (d, 1H, J=4.6 Hz),8.10 (s, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.57 (m, 2H), 7.13-7.6 (m,3H), 6.56 (d, 1H, J=8.8 Hz), 4.60 (s, 2H), 3.65 (s, 3H). LCMS: ret.time: 15.36 min.; purity: 94%; MS (m/e): 409 (MH⁺).

7.3.10275-Fluoro-N4-(indazoline-5-yl)-N2-(indazoline-6-yl)-2,4-pyrimidinediamine(R935270)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(indazoline-5-yl)-4-pyrimidineamine was reacted with6-aminoindazoline to produce5-fluoro-N4-(indazoline-5-yl)-N2-(indazoline-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.35 (s, 1H), 9.19 (s, 1H), 8.25 (d, 1H, J=4.1 Hz),8.12 (s, 1H), 8.01 (s, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.64 (d, 1H,J=8.8 Hz), 7.60 (dd, 2H, J=1.7 and 8.9 Hz), 7.51 (d, 1H, J=8.9 Hz), 7.21(dd, 1H, J=1.7 and 8.8 Hz). LCMS: ret. time: 13.45 min.; purity: 95%; MS(m/e): 361 (MH⁺).

7.3.10285-Fluoro-N4-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R935271)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-4-pyrimidineaminewas reacted with 3-(N-methylaminocarbonylmethyleneoxy)aniline to produce5-fluoro-N4-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.44 (s, 1H), 9.25 (s, 1H), 8.11 (d, 1H, J=3.5 Hz),8.03 (d, 1H, J=2.3 Hz), 7.90 (qt, 1H, J=4.6 Hz), 7.69 (d, 1H, J=1.2 Hz),7.47-7.42 (m, 1H), 7.33 (m, 1H), 7.26 (dd, 1H, J=1.2 and 8.2 Hz), 7.12(s, 1H), 7.09 (d, 1H, J=1.7 Hz), 6.97 (t, 1H, J=8.2H), 6.40 (dd, 1H,J=2.3 and 8.2 Hz), 5.25 (s, 2H), 4.26 (s, 2H), 2.61 (d, 3H, J=4.6 Hz).LCMS: ret. time: 15.45 min.; purity: 97%; MS (m/e): 462 (MH⁺).

7.3.10295-Fluoro-N2-(4-isopropoxyphenyl)-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine(R935276)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1H-pyrrol-1-yl)-4-pyrimidineamine was reacted with4-isopropoxyaniline to produce5-fluoro-N2-(4-isopropoxyphenyl)-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.69 (s, 1H), 9.03 (s, 1H), 8.06 (d, 1H, J=3.5 Hz),7.30 (d, 2H, J=9.3 Hz), 6.82 (t, 2H, J=2.3 Hz), 6.58 (d, 2H, J=9.3 Hz),6.11 (t, 2H, J=2.3 Hz), 4.41 (sept, 1H, J=5.8 Hz), 1.18 (d, 6H, J=5.8Hz). LCMS: ret. time: 21.21 min.; purity: 90%; MS (m/e): 328 (MH⁺).

7.3.1030 N2-(3,4-Ethylenedioxyphenyl)-5-Fluoro-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine(R935277)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1H-pyrrol-1-yl)-4-pyrimidineamine was reacted with3, 4-ethylenedioxyaniline to produce N2-(3,4-ethylenedioxyphenyl)-5-Fluoro-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 11.63 (s, 1H), 9.94 (s, 1H), 8.23 (d, 1H, J=4.7 Hz),6.86 (m, 4H), 6.58 (d, 1H, J=8.8 Hz), 6.12 (t, 2H, J=2.3 Hz), 4.15 (s,4H). LCMS: ret. time: 17.36 min.; purity: 96%; MS (m/e): 328 (MH⁺).

7.3.10315-Fluoro-N2-(3-hydroxyphenyl)-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine(R935278)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1H-pyrrol-1-yl)-4-pyrimidineamine was reacted with3-aminophenol to produce5-fluoro-N2-(3-hydroxyphenyl)-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.68 (s, 1H), 9.04 (s, 1H), 9.00 (s, 1H), 8.08 (d,1H, J=4.11 Hz), 7.01 (d, 1H, J=8.2 Hz), 6.84-6.75 (m, 4H), 6.22 (dd, 1H,J=1.2 and 8.2 Hz), 6.08 (t, 2H, J=2.3 Hz). LCMS: ret. time: 16.24 min.;purity: 94%; MS (m/e): 286 (MH⁺).

7.3.10325-Fluoro-N4-(indazoline-5-yl)-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R935279)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(indazoline-5-yl)-N2-[3-(-methoxycarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provide5-fluoro-N4-(indazoline-5-yl)-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 12.98 (s, 1H), 9.35 (s, 1H), 9.16 (s, 1H), 8.21 (s,1H), 8.07 (d, 1H, J=3.5 Hz), 7.97 (s, 1H), 7.90 (qt, 1H, J=4.7 Hz), 7.59(dd, 1H, J=8.8 Hz), 7.49 (d, 1H, J=8.8 Hz), 7.32-7.28 (m, 2H), 7.03 (t,1H, J=8.2 Hz), 6.45 (dd, 1H, J=1.7 and 8.2 Hz), 4.31 (s, 2H), 2.61 (d,3H, J=4.7 Hz). LCMS: ret. time: 12.92 min.; purity: 90%; MS (m/e): 408(MH⁺).

7.3.10335-Fluoro-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine(R935280)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1H-pyrrol-1-yl)-4-pyrimidineamine was reacted with3-(methoxycarbonylmethyleneoxy)aniline to produce5-fluoro-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 11.45 (s, 1H), 9.90 (s, 1H), 8.26 (d, 1H, J=4.7 Hz),7.07 (d, 1H, J=8.2 Hz), 7.68 (d, 1H, J=8.2 Hz), 6.94 (s, 1H), 6.85 (t,2H, J=2.3 Hz), 6.47 (dd, 1H, J=2.3 and 8.2 Hz), 6.12 (t, 2H, J=2.3 Hz),4.64 (s, 2H), 3.68 (s, 3H). LCMS: ret. time: 16.24 min.; purity: 92%; MS(m/e): 358 (MH⁺).

7.3.1034 5-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine (R935281)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N2-[3-(-methoxycarbonylmethyleneoxy)phenyl]-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provide5-fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.73 (s, 1H), 9.21 (s, 1H), 8.11 (d, 1H, J=4.1 Hz),7.89 (qt, 1H, J=4.7 Hz), 7.14 (d, 1H, J=8.2 Hz), 7.09 (s, 1H), 6.93 (t,1H, J=8.2 Hz), 6.84 (t, 2H, J=2.3 Hz), 6.40 (dd, 1H, J=2.3 and 8.2 Hz),6.09 (t, 2H, J=2.3 Hz), 4.29 (s, 2H), 2.63 (s, 3H, J=4.7 Hz). LCMS: ret.time: 16.16 min.; purity: 90%; MS (m/e): 357 (MH⁺).

7.3.1035 N2-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R935286)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine wasreacted with 6-amino-1-(2-ethoxycarbonylethyl)indazoline to provideN2-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆):δ 9.37 (s, 1H), 9.20 (s, 1H), 8.10 (d, 1H, J=3.5 Hz), 8.06 (s, 1H), 7.87(s, 1H), 7.53 (d, 1H, J=8.8 Hz), 7.33-7.21 (m, 3H), 6.77 (d, 1H, J=8.8Hz), 4.34 (t, 2H, J=6.4 Hz), 4.19 (s, 4H), 3.93 (qt, 2H, J=7.0 Hz), 2.82(t, 2H, J=6.4 Hz), 1.04 (t, 3H, J=7.0 Hz). LCMS: ret. time: 24.70 min.;purity: 90%; MS (m/e): 479 (MH⁺).

7.3.1036 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-2,4-pyrimidinediamine(R935287)

In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine was reacted withDIBAL-H to produce N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.35 (s, 1H), 9.19 (s, 1H), 8.09 (d, 1H, J=4.1 Hz),8.01 (s, 1H), 7.85 (s, 1H), 7.53 (d, 1H, J=8.8 Hz), 7.32-7.20 (m, 3H),6.77 (d, 1H, J=8.8 Hz), 4.20 (s, 4H), 3.27 (t, 2H, J=6.4 Hz), 3.27 (t,2H, J=6.4 Hz), 1.84 (q, 2H, J=6.4 Hz). LCMS: ret. time: 24.70 min.;purity: 90%; MS (m/e): 479 (MH⁺). LCMS: ret. time: 22.09 min.; purity:90%; MS (m/e): 437 (MH⁺).

7.3.1037 N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-6-yl]-2,4-pyrimidinediamine(R935288)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine and Me₂NH.HCl werereacted to provide N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.35 (s, 1H), 9.19 (s, 1H), 8.10 (d, 1H, J=3.5 Hz),8.02 (s, 1H), 7.86 (s, 1H), 7.81 (qt, 1H, J=4.7 Hz), 7.52 (d, 1H, J=8.2Hz), 7.34-7.22 (m, 3H), 6.77 (d, 1H, J=8.8 Hz), 4.33 (t, 2H, J=6.4 Hz),4.19 (s, 4H), 2.57 (t, 2H, J=6.4 Hz), 2.48 (d, 3H, J=4.7 Hz). LCMS: ret.time: 23.10 min.; purity: 93%; MS (m/e): 464 (MH⁺).

7.3.1038N4-[1-(2-Ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(isopropoxyphenyl)-2,4-pyrimidinediamine(R935289)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-isopropoxyphenyl)-4-pyrimidineamine was reactedwith 6-amino-1-(2-ethoxycarbonylethyl)indazoline to provideN2-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N4-(isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.74 (s, 1H), 10.55 (s, 1H), 8.35 (d, 1H, J=5.8Hz), 7.98 (s, 1H), 7.77 (s, 1H), 7.66 (d, 1H, J=8.8 Hz), 7.51 (d, 2H,J=8.8 Hz), 7.16 (dd, 1H, J=1.2 and 8.8 Hz), 6.85 (d, 2H, J=8.8 Hz), 4.55(sept, 1H, J=6.4 Hz), 4.31 (t, 2H, J=6.4 Hz), 3.93 (qt, 2H, J=7.0 Hz),2.80 (t, 2H, J=6.4 Hz), 1.22 (d, 6H, J=7.0 Hz), 1.02 (t, 3H, J=7.0 Hz).LCMS: ret. time: 26.84 min.; purity: 96%; MS (m/e): 479 (MH⁺).

7.3.10395-Fluoro-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine(R935290)

In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N4-(isopropoxyphenyl)-2,4-pyrimidinediaminewas reacted with DIBAL-H to produce5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.31 (s, 1H), 9.22 (s, 1H), 8.08 (d, 1H, J=4.1 Hz),7.98 (s, 1H), 7.85 (s, 1H), 7.62 (dd, 2H, J=3.5 and 8.8 Hz), 7.52 (d,1H, J=8.8 Hz), 7.27 (d, 1H, J=8.8 Hz), 6.86 (d, 2H, J=8.8 Hz), 4.55(sept, 1H, J=7.0 Hz), 4.49 (t, 1H, J=5.3 Hz), 4.14 (t, 2H, J=6.4 Hz),3.26 (t, 2H, J=6.4 Hz), 1.84 (q, 2H, J=6.4 Hz), 1.24 (d, 6H, J=7.0 Hz).LCMS: ret. time: 24.13 min.; purity: 97%; MS (m/e): 437 (MH⁺).

7.3.10405-Fluoro-N4-(4-isopropoxyphenyl)-N2-[1-[2(N-methylamino)carbonyl]ethyl-indazoline-6-yl]-2,4-pyrimidinediamine(R935291)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N4-(isopropoxyphenyl)-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provide5-fluoro-N4-(4-isopropoxyphenyl)-N2-[1-[2(N-methylamino)carbonyl]ethyl-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.32 (s, 1H), 9.24 (s, 1H), 8.10 (d, 1H, J=3.5 Hz),7.99 (s, 1H), 7.85 (s, 1H), 7.80 (qt, 1H, J=4.7 Hz), 7.63 (d, 2H, J=8.8Hz), 7.52 (d, 1H, J=8.8 Hz), 7.28 (d, 1H, J=8.8 Hz), 6.84 (d, 2H, J=8.8Hz), 4.54 (sept, 1H, J=5.8 Hz), 4.30 (t, 2H, J=6.4 Hz), 2.55 (t, 2H, 7.4Hz), 2.48 (d, 3H, J=4.7 Hz), 1.24 (d, 6H, J=6H). LCMS: ret. time: 23.68min.; purity: 95%; MS (m/e): 464 (MH⁺).

7.3.1041N4-[1-(2-Ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R935292)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with6-amino-1-(2-ethoxycarbonylethyl)indazoline to provideN4-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.35 (s, 1H), 10.21 (s, 1H), 8.29 (d, 1H, J=5.3Hz), 7.96 (s, 1H), 7.90 (s, 1H), 7.63 (d, 1H, J=8.8 Hz), 7.20-7.06 (m,4H), 6.58 (d, 1H, J=8.2 Hz), 4.33 (t, 2H, J=6.4 Hz), 3.94 (qt, 2H, J=7.0Hz), 2.82 (t, 2H, J=6.4 Hz), 1.03 (t, 3H, J=7.0 Hz). LCMS: ret. time:22.73 min.; purity: 94%; MS (m/e): 437 (MH⁺).

7.3.10425-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-2,4-pyrimidinediamine(R935293)

In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediaminewas reacted with DIBAL-H to produce5-fluoro-N4-(3-hydroxyphenyl)-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.38 (s, 1H), 9.35 (s, 1H), 9.26 (s, 1H), 8.13 (d,1H, J=4.1 Hz), 8.05 (s, 1H), 7.85 (s, 1H), 7.52 (d, 1H, J=8.2 Hz), 7.28(d, 2H, J=8.8 Hz), 7.12 (d, 1H, J=1.7 Hz), 7.08 (t, 1H, J=8.2 Hz), 6.49(d, 1H, J=8.2 Hz), 4.15 (t, 2H, J=7.0 Hz), 3.26 (t, 2H, J=6.4 Hz), 1.85(q, 2H, J=6.4 Hz). LCMS: ret. time: 24.70 min.; purity: 90%; MS (m/e):479 (MH⁺). LCMS: ret. time: 20.37 min.; purity: 98%; MS (m/e): 395(MH⁺).

7.3.10435-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2-(N-methylaminocarbonyl)ethyl]-indazoline-6-yl]-2,4-pyrimidinediamine(R935294)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provide5-fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2-(N-methylaminocarbonyl)ethyl]-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.36 (s, 1H), 9.33 (s, 1H), 9.25 (s, 1H), 8.14 (d,1H, J=3.5 Hz), 8.05 (s, 1H), 7.85 (s, 1H), 7.78 (qt, 1H, J=4.7 Hz), 7.52(d, 1H, J=8.8 Hz), 7.30 (d, 2H, J=8.8 Hz), 7.11 (d, 1H, J=2.3 Hz), 7.07(t, 1H, J=8.2 Hz), 6.47 (d, 1H, J=8.2 Hz), 4.32 (t, 2H, J=6.4 Hz), 2.57(t, 2H, J=6.4 Hz), 2.48 (d, 3H, J=4.7 Hz). LCMS: ret. time: 20.18 min.;purity: 93%; MS (m/e): 422 (MH⁺).

7.3.1044N4-[1-(2-Ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine(R935295)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(2-methoxycarbonylbenzofur-5-yl)-4-pyrimidineaminewas reacted with 6-amino-1-(2-ethoxycarbonylethyl)indazoline to provideN4-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediaminePurification of the crude gave two products.

N4-[1-(2-Ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine(R935295)

¹H NMR (DMSO-d₆): δ 9.54 (s, 1H), 9.41 (s, 1H), 8.21 (app d, 1H, J=1.7Hz), 8.17 (d, 1H, J=3.5 Hz), 8.01 (s, 1H), 7.86 (s, 1H), 7.83-7.80 (m2H), 7.68 (d, 1H, J=8.8 Hz), 7.59 (s, 1H), 7.52 (d, 1H, J=8.2 Hz), 7.25(d, 1H, J=8.2 Hz), 4.12 (t, 2H, J=6.4 Hz), 3.91 (qt, 2H, J=7.0 Hz), 3.88(s, 3H), 2.72 (t, 2H, J=6.4 Hz), 1.02 (t, 3H, J=7.0 Hz). LCMS: ret.time: 25.67 min.; purity: 91%; MS (m/e): 519 (MH⁺) and

N4-[1-(2-carboxyethyl)indazoline-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine(R935296)

¹H NMR (DMSO-d₆): δ 9.54 (s, 1H), 9.39 (s, 1H), 8.23 (app d, 1H, J=1.7Hz), 8.17 (d, 1H, J=3.5 Hz), 8.00 (s, 1H), 7.86 (s, 1H), 7.83-7.80 (m2H), 7.68 (d, 1H, J=8.8 Hz), 7.58 (s, 1H), 7.52 (d, 1H, J=8.2 Hz), 7.28(d, 1H, J=8.2 Hz), 4.13 (t, 2H, J=6.4 Hz), 3.88 (s, 3H), 2.67 (t, 2H,J=6.4 Hz). LCMS: ret. time: 23.28 min.; purity: 91%; MS (m/e): 491(MH⁺).

7.3.10455-Fluoro-N4-[2-(N-methylaminocarbonyl)benzofuran-5-yl]-N2-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-6-yl]-2,4-pyrimidinediamine(R935297)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provide5-fluoro-N4-[2-(N-methylaminocarbonyl)benzofuran-5-yl]-N2-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.00 (s, 1H), 9.90 (s, 1H), 8.70 (qt, 1H, J=4.7Hz), 8.24 (d, 1H, J=4.1 Hz), 8.12 (d, 1H, J=1.7 Hz), 7.911 (s, 1H), 7.86(s, 1H), 7.81 (qt, 1H, J=4.7 Hz), 7.71 (d, 2H, J=1.7 and 8.8 Hz), 7.57(dd, 1H, J=3.5 and 8.8 Hz), 7.35 (s, 1H), 7.26 (dd, 1H, J=3.5 and 8.8Hz), 4.19 (t, 2H, J=7.0 Hz), 2.53 (t, 2H, J=7.0 Hz), 2.47 (d, 6H, J=4.7Hz). LCMS: ret. time: 20.18 min.; purity: 89%; MS (m/e): 503 (MH⁺).

7.3.10465-Fluoro-N4-(4-isopropoxyphenyl)-N2-(2-methyl-indazoline-5-yl)-2,4-pyrimidinediamine(R935298)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-isopropoxyphenyl)-4-pyrimidineamine and5-amino-2-methylindazoline were reacted to give5-fluoro-N4-(4-isopropoxyphenyl)-N2-(2-methyl-indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.15 (s, 1H), 9.03 (s, 1H), 8.03-8.00 (m, 3H), 7.60(dd, 2H, J=4.1 and 8.8 Hz), 7.42 (d, 1H, J=9.3 Hz), 7.31 (d, 1H, J=9.3Hz), 6.86 (d, 2H, J=8.8 Hz), 4.57 (sept, 1H, J=6.4 Hz), 4.08 (s, 3H),1.26 (d, 6H, J=6.4 Hz), LCMS: ret. time: 23.89 min.; purity: 98%; MS(m/e): 393 (MH⁺).

7.3.10475-Fluoro-N4-(3-hydroxyphenyl)-N2-(2-methy-indazoline-5-yl)-2,4-pyrimidinediamine(R935299)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with5-amino-2-methylindazoline to produce5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methy-indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.35 (s, 1H), 10.30 (s, 1H), 9.62 (br s, 1H), 8.22(d, 1H, J=5.3 Hz), 8.13 (s, 1H), 7.85 (s, 1H), 7.49 (d, 1H, J=8.8 Hz),7.17 (dd, 1H, J=1.7 and 9.3 Hz), 7.08 (d, 2H, J=5.3 Hz), 7.03 (s, 1H),6.64-6.60 (m, 1H), 4.09 (s, 3H). LCMS: ret. time: 20.01 min.; purity:97%; MS (m/e): 351 (MH⁺).

7.3.1048 N4-(3,4-Ethyelenedioxyphenyl)-5-fluoro-N2-(2-methy-indazoline-5-yl)-2,4-pyrimidinediamine(R935300)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine wasreacted with 5-amino-2-methylindazoline to produce N4-(3,4-ethyelenedioxyphenyl)-5-fluoro-N2-(2-methy-indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.64 (s, 1H), 10.62 (s, 1H), 8.22 (d, 1H, J=5.3Hz), 8.21 (s, 1H), 7.77 (s, 1H), 7.58 (d, 1H, J=9.3 Hz), 7.23-7.19 (m,2H), 7.10 (dd, 1H, J=2.3 and 8.8 Hz), 6.78 (d, 1H, J=8.8 Hz), 4.21 (s,3H), 4.15 (s, 4H). LCMS: ret. time: 21.77 min.; purity: 92%; MS (m/e):393 (MH⁺).

7.3.1049 N2-[1-(2-Ethoxycarbonylethyl)indazoline-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R935301)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine wasreacted with 5-amino-1-(2-ethoxycarbonylethyl)indazoline to provideN2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆):δ 9.15 (s, 1H), 9.13 (s, 1H), 8.10, (s, 1H), 8.04 (d, 1H, J=3.5 Hz),7.83 (s, 1H), 7.50 (s, 2H), 7.30 (d, 1H, J=2.3 and 8.8 Hz), 6.79 (d, 1H,J=8.8 Hz), 4.55 (t, 2H, J=6.4 Hz), 4.22 (s, 4H), 3.97 (qt, 2H, J=7.0Hz), 2.88 (t, 2H, J=6.4 Hz), 1.06 (t, 3H, J=7.0 Hz). LCMS: ret. time:25.19 min.; purity: 93%; MS (m/e): 479 (MH⁺).

7.3.1050 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine(R935302)

In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine was reacted withDIBAL-H to produce N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.14 (s, 1H), 9.13 (s, 1H), 8.09 (s, 1H), 8.03 (d,1H, J=4.1 Hz), 7.82 (s, 1H), 7.48 (s, 2H), 7.30 (d, 1H, J=2.3 Hz), 7.18(dd, 1H, J=2.3 and 8.8 Hz), 6.78 (d, 1H, J=8.8 Hz), 4.59 (t, 1H, J=6.4Hz), 4.37 (t, 2H, J=6.4 Hz), 4.22 (s, 4H), 3.34 (t, 2H, J=6.4 Hz), 1.84(q, 2H, J=6.4 Hz). LCMS: ret. time: 22.33 min.; purity: 100%; MS (m/e):437 (MH⁺).

7.3.1051N4-[1-(2-Ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R935303)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with5-amino-1-(2-ethoxycarbonylethyl)indazoline to provideN4-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.50 (s, 1H), 10.46 (s, 1H), 9.62 (br s 1H), 8.28(d, 1H, J=5.8 Hz), 7.96 (s, 2H), 7.65 (d, 1H, J=8.8 Hz), 7.36 (dd, 1H,J=1.7 and 8.8 Hz), 7.15-7.08 (m, 3H), 6.67-6.64 (m, 1H), 4.59 (t, 2H,J=6.4 Hz), 3.97 (qt, 2H, J=7.0 Hz), 2.89 (t, 2H, J=6.4 Hz), 1.06 (t, 3H,J=7.0 Hz). LCMS: ret. time: 23.68 min.; purity: 97%; MS (m/e): 437(MH⁺).

7.3.10525-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine(R935304)

In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediaminewas reacted with DIBAL-H to produce5-fluoro-N4-(3-hydroxyphenyl)-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.39 (s, 1H), 9.18 (s, 1H), 9.15 (s, 1H), 8.20 (s,1H), 8.07 (d, 1H, J=4.1 Hz), 7.84 (s, 1H), 7.46 (s, 2H), 7.24 (d, 1H,J=8.2 Hz), 7.11-7.06 (m, 2H), 6.53 (d, 1H, J=8.8 Hz), 4.56 (t, 1H, J=4.7Hz), 4.37 (t, 2H, J=6.4 Hz), 3.34 (t, 2H, J=6.4 Hz), 1.92 (q, 2H, J=6.4Hz). LCMS: ret. time: 24.70 min.; purity: 90%; MS (m/e): 479 (MH⁺).LCMS: ret. time: 20.89 min.; purity: 98%; MS (m/e): 395 (MH⁺).

7.3.10535-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-5-yl]-2,4-pyrimidinediamine(R935305)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provide5-fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.39 (s, 1H), 9.18 (s, 1H), 9.15 (s, 1H), 8.19 (s,1H), 8.06 (d, 1H, J=3.5 Hz), 7.84 (s, 1H), 7.82 (qt. 1H, J=4.7 Hz), 7.46(t, 2H, J=8.2 Hz), 7.25 (d, 1H, J=8.2 Hz), 7.11 (d, 1H, J=8.2 Hz), 7.10(d, 1H, J=8.2 Hz), 6.53 (t, 1H, J=8.2 Hz), 4.51 (t, 2H, J=7.0 Hz), 2.61(t, 2H, J=7.0 Hz), 2.49 (d, 3H, J=4.7 Hz). LCMS: ret. time: 20.66 min.;purity: 95%; MS (m/e): 422 (MH⁺).

7.3.1054N4-[1-(2-Ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine(R935306)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-isopropoxyphenyl)-4-pyrimidineamine was reactedwith 5-amino-1-(2-ethoxycarbonylethyl)indazoline to provideN2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.48 (s, 1H), 10.41 (s, 1H), 8.25 (d, 1H, J=5.8Hz), 7.93 (s, 1H), 7.84 (s, 1H), 7.66 (d, 1H, J=8.8 Hz), 7.49 (d, 2H,J=8.8 Hz), 7.36 (dd, 1H, J=2.3 and 8.8 Hz), 6.86 (d, 2H, J=8.8 Hz), 4.59(t, 2H, J=6.4 Hz), 4.57 (sept, 1H, J=7.0 Hz), 3.96 (qt, 2H, J=7.0 Hz),2.89 (t, 2H, J=6.4 Hz), 1.23 (d, 6H, J=7.0 Hz), 1.05 (t, 3H, J=7.0 Hz).LCMS: ret. time: 27.39 min.; purity: 98%; MS (m/e): 479 (MH⁺).

7.3.10555-Fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine(R935307)

In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediaminewas reacted with DIBAL-H to produce5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.16 (s, 1H), 9.10 (s, 1H), 8.09 (s, 1H), 8.03 (d,1H, J=4.1 Hz), 7.79 (s, 1H), 7.57 (d, 2H, J=8.8 Hz), 7.46 (t, 2H), 6.87(d, 2H, J=8.8 Hz), 4.60-4.52 (m, 2H), 4.37 (t, 2H, J=6.4 Hz), 3.34 (t,2H, J=6.4 Hz), 1.84 (q, 2H, J=6.4 Hz), 1.24 (d, 6H, J=7.0 Hz). LCMS:ret. time: 23.71 min.; purity: 98%; MS (m/e): 437 (MH⁺).

7.3.10565-Fluoro-N4-(2-hydroxymethylbenzofur-5-yl)-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-2,4-pyrimidinediamine(R935308)

In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-[1-(2-Ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediaminewas reacted with DIBAL-H to produce5-fluoro-N4-(2-hydroxymethylbenzofur-5-yl)-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.35 (s, 1H), 9.33 (s, 1H), 8.12 (d, 1H, J=3.5 Hz),7.99 (d, 1H, J=1.7 Hz), 7.95 (s, 1H), 7.84 (s, 1H), 7.55-7.49 (m, 3H),7.28 (d, 1H, J=8.8 Hz), 6.62 (s, 1H), 5.46 (t, 1H, J=5.8 Hz), 4.55 (d,2H, J=5.8 Hz), 4.45 (t, 1H, J=4.7 Hz), 3.96 (t, 2H, J=6.4 Hz), 3.20 (t,2H, J=6.4 Hz), 1.76 (q, 2H, J=6.4 Hz). LCMS: ret. time: 20.86 min.;purity: 99%; MS (m/e): 449 (MH⁺).

7.3.1057 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-5-yl]-2,4-pyrimidinediamine(R935309)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine and Me₂NH.HCl werereacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.12 (s, 1H), 9.11 (s, 1H), 8.09 (s, 1H), 8.03 (d,1H, J=3.5 Hz), 7.82 (s, 2H), 7.47 (s, 2H), 7.32-7.30 (m, 1H), 7.22-7.17(m, 1H), 6.80 (d, 1H, J=8.8 Hz), 4.51 (t, 2H, J=7.0 Hz), 4.22 (s, 4H),2.62 (t, 2H, J=7.0 Hz), 2.49 (d, 3H, J=4.7 Hz). LCMS: ret. time: 18.67min.; purity: 100%; MS (m/e): 464 (MH⁺).

7.3.10585-Fluoro-N4-(4-isopropoxyphenyl)-N2-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-5-yl]-2,4-pyrimidinediamine(R935310)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provide5-fluoro-N4-(4-isopropoxyphenyl)-N2-[1-[2(N-methylaminocarbonyl)ethyl]indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.18 (s, 1H), 9.09 (s, 1H), 8.08 (s, 1H), 8.02 (d,1H, J=4.1 Hz), 7.82 (qt, 1H, J=4.7 Hz), 7.79 (s, 1H), 7.57 (d, 2H, J=8.8Hz), 7.45 (d, 2H, J=8.8 Hz), 6.87 (d, 2H, J=8.8 Hz), 4.57 (q, 2H, J=5.8Hz), 4.51 (t, 2H, J=7.0 Hz), 2.61 (t, 2H, J=7.0 Hz), 2.47 (d, 3H, J=4.7Hz), 1.26 (d, 6H, J=5.8 Hz). LCMS: ret. time: 17.14 min.; purity: 99%;MS (m/e): 464 (MH⁺).

7.3.1059 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine(R935320)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine wasreacted with 6-amino-1-(2-methoxy-3-carbomethoxybenzyl)indazoline toprovide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.36 (s, 1H), 9.18 (s, 1H), 8.08 (d, 1H, J=3.5 Hz),8.04 (s, 1H), 7.56 (d, 1H, J=8.2 Hz), 7.45 (d, 1H, J=1.8 Hz), 7.43-7.38(m, 1H), 7.36-7.34 (m, 1H), 7.30 (dd, 1H, J=1.7 and 8.8 Hz), 7.20 (dd,1H, J=2.3 and 8.8 Hz), 6.75 (d, 1H, J=8.8 Hz), 6.68 (d, 1H, J=8.2 Hz),6.48 (dd, 1H, J=1.7 and 8.2 Hz), 5.39 (s, 2H), 4.16 (s, 4H), 3.83 (s,3H), 3.79 (s, 3H). LCMS: ret. time: 29.92 min.; purity: 80%; MS (m/e):557 (MH⁺).

7.3.10605-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine(R935321)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with6-amino-1-(2-methoxy-3-carbomethoxybenzyl)indazoline to provide5-fluoro-N4-(3-hydroxyphenyl)-N2-[1-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.37 (s, 1H), 9.31 (s, 1H), 9.23 (s, 1H), 8.11 (d,1H, J=3.5 Hz), 8.08 (s, 1H), 7.93 (s, 1H), 7.57 (d, 1H, J=8.8 Hz), 7.45(d, 1H, J=1.7 Hz), 7.40 (dd, 1H, J=1.7 and 8.8 Hz), 7.33-7.27 (2H), 7.13(t, 1H, J=1.7 HZ), 7.03 (t, 2H, J=8.2 Hz), 6.67 (d, 1H, J=8.2 Hz), 6.45(dd, 1H, J=1.7 and 8.2 Hz), 5.37 (s, 2H), 3.83 (s, 3H), 3.79 (s, 3H).LCMS: ret. time: 28.80 min.; purity: 92%; MS (m/e): 515 (MH⁺).

7.3.10615-Fluoro-N4-(4-isopropoxyphenyl)-N2-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-6-yl]-2,4-pyrimidinediamine(R935322)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-isopropoxyphenyl)-4-pyrimidineamine was reactedwith6-amino-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline toprovide5-fluoro-N4-(4-isopropoxyphenyl)-N2-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-6-yl]-2,4-pyrimidinediamine.¹HNMR (DMSO-d₆): δ 9.60 (s, 2H), 8.11 (d, 1H, J=4.1 Hz), 8.00-7.92 (m,3H), 7.61-7.53 (m, 4H), 7.47-7.24 (m, 5H), 6.81 (d, 2H, J=8.8 Hz), 6.68(d, 1H, J=8.2 Hz), 5.34 (s, 2H), 4.48 (sept, 1H, J=5.9 Hz), 3.82 (s,3H), 2.55 (s, 3H), 1.21 (d, 6H, J=5.9 Hz). LCMS: ret. time: 30.57 min.;purity: 95%; MS (m/e): 696 (MH⁺).

7.3.1062 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-6-yl]-2,4-pyrimidinediamine(R935323)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine wasreacted with6-amino-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline toprovide N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.53 (s, 1H), 9.41 (s, 1H), 8.05 (d, 1H, J=4.1 Hz),7.96-7.90 (m, 3H), 7.55 (d, 1H, J=8.8 Hz), 7.49 (dd, 1H, J=7.6 Hz),7.42-7.20 (m, 6H), 7.14-7.10 (m, 1H), 6.69 (d, 1H, J=8.2 Hz), 6.60 (d,1H, J=8.8 Hz), 5.33 (s, 2H), 4.10 (s, 4H), 3.77 (s, 3H), 2.50 (s, 3H).LCMS: ret. time: 32.11 min.; purity: 93%; MS (m/e): 696 (MH⁺).

7.3.10635-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-6-yl]-2,4-pyrimidinediamine(R935324)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with6-amino-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline toprovide5-fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.64 (s, 1H), 9.56 (s, 1H), 8.15 (d, 1H, J=4.1 Hz),8.00 (s, 1H), 7.97 (d, 2H, J=8.8 Hz), 7.60 (d, 1H, J=8.8 Hz), 7.53 (d,1H, J=1.2 and 8.8 Hz), 7.47-7.23 (m, 6H), 7.11 (t, 1H, J=1.7 Hz), 7.03(t, 1H, J=8.2 Hz), 6.62 (d, 1H, J=8.2 Hz), 6.48 (dd, 1H, J=1.7 and 8.2Hz), 5.36 (s, 2H), 3.82 (s, 3H), 2.55 (s, 3H). LCMS: ret. time: 29.79min.; purity: 92%; MS (m/e): 654 (MH⁺).

7.3.1064 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine(R935336)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine wasreacted with 6-amino-2-(2-methoxy-3-carbomethoxybenzyl)indazoline toprovide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.16 (s, 1H), 9.14 (s, 1H), 8.24 (s, 1H), 8.06 (s, 1h), 8.04 (d, 1H, J=3.5 Hz), 7.51 (d, 2H, J=7.7 Hz), 7.49 (s, 1H),7.29-7.26 (m, 2H), 7.19 (d, 1H, J=7.7 Hz), 6.92 (d, 1H, J=8.8 Hz), 6.76(d, 1H, J=8.2 Hz), 5.58 (s, 2H), 4.22 (s, 4H), 3.92 (s, 3H), 3.82 (s,3H). LCMS: ret. time: 10.91 min.; purity: 91%; MS (m/e): 557 (MH⁺).

7.3.10655-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine(R935337)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with6-amino-2-(2-methoxy-3-carbomethoxybenzyl)indazoline to provide5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.31 (s, 1H), 9.17 (s, 1H), 9.15 (s, 1H), 8.26 (s,1H), 8.09 (d, 1H, J=5.8 Hz), 8.08 (s, 1H), 7.52 (app t, 3H, J=7.6 Hz),7.42 (d, 1H, J=8.2 Hz), 7.23 (d, 1H, J=8.2 Hz), 7.08 (app s,1H), 7.03(d, 1H, J=8.2 Hz), 6.93 (d, 1H, J=7.6 Hz), 6.43 (d, 1H, J=8.2 Hz), 5.57(s, 2H), 3.90 (s, 3H), 3.82 (s, 3H). LCMS: ret. time: 10.51 min.;purity: 93%; MS (m/e): 515 (MH⁺).

7.3.10665-Fluoro-N4-(4-isopropoxyphenyl)-N2-[2-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine(R935338)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-isopropoxyphenyl)-4-pyrimidineamine was reactedwith 6-amino-2-(2-methoxy-4-carbomethoxybenzyl)indazoline to provide5-fluoro-N4-(4-isopropoxyphenyl)-N2-[2-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.20 (s, 1H), 9.16 (s, 1H), 8.26 (s, 1H), 8.16 (s,1H), 8.06 (d, 1H, J=3.5 Hz), 7.66 (d, 2H, J=8.8 Hz), 7.52-7.48 (m, 3H),7.15 (d, 1H, J=8.2 Hz), 6.86 (d, 2H, J=8.8 Hz), 6.81 (d, 1H, J=8.8 Hz),5.56 (s, 2H), 4.46 (sept, 1H, J=5.9 Hz), 3.91 (s, 3H), 3.82 (s, 3H),1.17 (d, 6H, J=5.9 Hz). LCMS: ret. time: 11.94 min.; purity: 90%; MS(m/e): 557 (MH⁺).

7.3.1067 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-5-yl]-2,4-pyrimidinediamine(R935339)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine wasreacted with5-amino-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline toprovide N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.57 (br s, 2H), 8.08 (d, 1H, J=3.5 Hz), 8.01 (s,1H), 7.99 (d, 1H, J=1.0 Hz), 7.95 (s, 1H), 7.59-7.32 (m, 3H), 7.45-7.32(m, 4H), 7.27-7.24 (m, 1H), 7.17-7.12 (m, 1H), 6.74 (d, 1H, J=8.7 Hz),6.65 (d, 1H, J=8.7 Hz), 5.58 (s, 2H), 4.15 (s, 4H), 3.88 (s, 3H), 2.56(s, 3H). LCMS: ret. time: 11.33 min.; purity: 98%; MS (m/e): 696 (MH⁺).

7.3.10685-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-5-yl]-2,4-pyrimidinediamine(R935340)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with5-amino-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline toprovide5-fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.57 (s, 1H), 9.48 (s, 1H), 8.13 (app s, 2H), 8.00(d, 1H, J=8.2 Hz), 7.94 (s, 1H), 7.59-7.32 (m, 7H), 7.18 (d, 1H, J=8.2Hz), 7.06 (app t, 3H, J=8.8 Hz), 6.64 (d, 1H, J=8.2 Hz), 6.55 (d, 1H,J=8.2 Hz), 5.57 (s, 2H), 3.88 (s, 3H), 2.56 (s, 3H). LCMS: ret. time:10.16 min.; purity: 97%; MS (m/e): 654 (MH⁺).

7.3.1069N4-(4-Chlorophenyl)-5-fluoro-N2-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine(R935351)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(4-chlorophenyl)-5-fluoro 4-pyrimidineamine and1-methyl-5-aminoindazoline were reacted to giveN4-(4-chlorophenyl)-5-fluoro-N2-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.86 (s, 1H), 9.61 (s, 1H), 8.17 (d, 1H, J=4.1 Hz),8.00 (s, 1H), 7.88 (s, 1H), 7.78 (d, 2H, J=8.8 Hz), 7.57 (d, 1H, J=8.8Hz), 7.43 (d, 1H, J=8.8 Hz), 7.34 (d, 2H, J=8.8 Hz), 4.00 (s, 3H). LCMS:ret. time: 10.64 min.; purity: 94%; MS (m/e): 369 (MH⁺).

7.3.1070N4-(4-Chlorophenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine(R935352)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(4-chlorophenyl)-5-fluoro 4-pyrimidineamime and6-aminoindazoline were reacted to giveN4-(4-chlorophenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.18 (s, 1H), 10.02 (s, 1H), 8.26 (d, 1H, J=4.1Hz), 7.98 (s, 1H), 7.84 (d, 1H, J=8.8 Hz), 7.82 (d, 2H, J=8.8 Hz), 7.65(d, 1H, J=8.8 Hz), 7.35 (d, 2H, J=8.8 Hz), 7.19 (d, 1H, J=8.8 Hz). LCMS:ret. time: 10.80 min.; purity: 90%; MS (m/e): 355 (MH⁺).

7.3.1071N4-(4-Chlorophenyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine(R935353)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(4-chlorophenyl)-5-fluoro-4-pyrimidineamine was reacted with5-amino-1-(2-ethoxycarbonylethyl)indazoline to provideN4-(4-chlorophenyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.37 (s, 1H), 10.17 (s, 1H), 8.26 (d, 1H, J=5.3Hz), 7.96 (s, 1H), 7.88 (s, 1H), 7.33-7.66 (m, 3H), 7.40 (d, 1H, J=8.8Hz), 7.35 (d, 2H, J=8.8 Hz), 4.61 (t, 2H, J=6.4 Hz), 3.97 (qt, 2H, J=7.0Hz), 2.91 (t, 2H, J=6.4 Hz), 1.05 (t, 3H, J=7.0 Hz). LCMS: ret. time:11.85 min.; purity: 95%; MS (m/e): 455 (MH⁺).

7.3.1072N4-(3-Chloro-4-trifluoromethoxy-phenyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine(R935354)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3-chloro-trifluoromethoxy-phenyl)-5-fluoro-4-pyrimidineaminewas reacted with 5-amino-1-(2-ethoxycarbonylethyl)indazoline to provideN4-(3-chloro-4-trifluoromethoxy-phenyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.63 (s, 1H), 9.30 (s, 1H), 8.17 (d, 1H, J=3.5 Hz),8.10 (t, 1H, J=2.3 Hz), 8.01 (s, 1H), 7.87 (s, 1H), 7.86 (d, 1H, J=8.2Hz), 7.57 (d, 1H, J=9.4 Hz), 7.47 (t, 2H, J=10.0 Hz), 4.56 (t, 2H, J=6.9Hz), 3.97 (qt, 2H, J=7.0 Hz), 2.88 (t, 2H, J=6.9 Hz), 1.06 (t, 3H, J=7.0Hz). LCMS: ret. time: 14.4 min.; purity: 95%; MS (m/e): 539 (MH⁺).

7.3.1073 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine(R935355)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-dichlorophenyl)-5-fluoro 4-pyrimidineamime and1-methyl-5-aminoindazoline were reacted to give N4-(3,4-dichlorophenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.63 (s, 1H), 9.35 (s, 1H), 8.17 (d, 1H, J=3.5 Hz),8.08 (s, 1H), 8.01 (s, 1H), 7.86 (s, 1H), 7.79 (d, 1H, J=8.8 Hz), 7.53(d, 2H, J=8.2 Hz), 7.47 (d, 1H, J=8.2 Hz), 3.99 (s, 3H). LCMS: ret.time: 12.30 min.; purity: 98%; MS (m/e): 404 (MH⁺).

7.3.10745-Fluoro-N2-(1-methylindazoline-5-yl)-N4-(3-trifluoromethoxypheny)-2,4-pyrimidinediamine(R935356)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-trifluoromethoxyphenyl)-4-pyrimidineamime and1-methyl-5-aminoindazoline were reacted to give5-fluoro-N2-(1-methylindazoline-5-yl)-N4-(3-trifluoromethoxypheny)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.37 (s, 1H), 10.17 (s, 1H), 8.25 (d, 1H, J=4.1Hz), 7.92 (s, 2H), 7.84 (d, 1H, J=9.4 Hz), 7.75 (s, 1H), 7.59 (d, 1H,J=8.8 Hz), 7.45 (d, 1H, J=9.4 Hz), 7.38 (d, 1H, J=9.4 Hz), 7.08 (d, 1H,J=8.8 Hz), 3.99 (s, 3H). LCMS: ret. time: 12.13 min.; purity: 94%; MS(m/e): 419 (MH⁺).

7.3.1075 N4-(3,4-Difluoromethylendioxyphenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine(R935357)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineamime and1-methyl-5-aminoindazoline were reacted to give N4-(3,4-difluoromethylendioxyphenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.84 (s, 1H), 9.54 (s, 1H), 8.16 (d, 1H, J=4.1 Hz),8.00 (s, 2H), 7.87 (s, 1H), 7.55-7.32 (m, 4H), 3.99 (s, 3H). LCMS: ret.time: 11.26 min.; purity: 96%; MS (m/e): 415 (MH⁺).

7.3.1076 N4-(3,4-Difluorophenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine(R935358)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-difluorophenyl)-5-fluoro-4-pyrimidineamime and1-methyl-5-aminoindazoline were reacted to give N4-(3,4-difluorophenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.50 (s, 1H), 9.27 (s, 1H), 8.13 (d, 1H, J=4.1 Hz),8.08 (app s, 2H), 7.85 (s, 1H), 7.50 (app s, 3H), 7.37 (q, 1H, J=9.4Hz), 3.99 (s, 3H). LCMS: ret. time: 10.42 min.; purity: 90%; MS (m/e):371 (MH⁺).

7.3.1077N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine(R935359)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamimeand 1-methyl-5-aminoindazoline were reacted to giveN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.79 (s, 1H), 9.45 (s, 1H), 8.19 (d, 1H, J=4.1 Hz),8.09 (t, 1H, J=2.8 Hz), 8.00 (s, 1H), 7.85-7.81 (m, 2H), 7.51 (d, 1H,J=8.8 Hz), 7.48-7.44 (m, 2H), 3.99 (s, 3H). LCMS: ret. time: 13.14 min.;purity: 92%; MS (m/e): 453 (MH⁺).

7.3.1078N2-[1-(2-Ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine(R935360)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-trifluoromethoxyphenyl)-4-pyrimidineamine wasreacted with 5-amino-1-(2-ethoxycarbonylethyl)indazoline to provideN2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.55 (s, 1H), 9.26 (s, 1H), 8.15 (d, 1H, J=3.5 Hz),8.05 (s, 1H), 7.95 (d, 1H, J=8.2 Hz), 7.88 (s, 1H), 7.78 (s, 1H), 7.58(dd, 1H, J=8.8 and 7.4 Hz), 7.39 (t, 1H, J=8.2 Hz), 7.01 (d, 1H, J=8.8Hz), 4.56 (t, 2H, J=7.0 Hz), 3.97 (q, 4H, J=7.0 Hz), 2.88 (t, 2H, J=7.0Hz), 1.06 (t, 3H, J=7.0 Hz). LCMS: ret. time: 13.22 min.; purity: 95%;MS (m/e): 505 (MH⁺).

7.3.10795-Fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]indazoline-5-yl]-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine(R935361)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provide5-fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]indazoline-5-yl]-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.55 (s, 1H), 9.25 (s, 1H), 8.15 (d, 1H, J=3.5 Hz),8.04 (s, 1H), 7.96 (d, 1H, J=8.2 Hz), 7.87 (s, 1H), 7.83 (qt, 1H, J=4.9Hz), 7.70 (s, 1H), 7.49 (dd, 2H, J=8.2 and 9.4 Hz), 7.40 (d, 1H, J=8.8Hz), 7.01 (d, 1H, J=8.8 Hz), 4.52 (t, 2H, J=7.0 Hz), 2.63 (t, 2H, J=7.0Hz), 2.49 (d, 3H, J=4.7 Hz). LCMS: ret. time: 10.00 min.; purity: 100%;MS (m/e): 490 (MH⁺).

7.3.10805-Fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine(R935362)

In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediaminewas reacted with DIBAL-H to produce5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.55 (s, 1H), 9.24 (s, 1H), 8.15 (d, 1H, J=2.9 Hz),8.05 (s, 1H), 7.92 (d, 1H, J=7.6 Hz), 7.87 (s, 1H), 7.78 (s, 1H), 7.50(s, 2H), 7.39 (t, 1H, J=8.2 Hz), 7.01 (d, 1H, J=7.6 Hz), 4.56 (t, 1H,J=5.2 Hz), 4.38 (t, 2H, J=7.0 Hz), 3.35 (dd, 2H, J=5.2 and 7.0 Hz), 1.84(qt, 2H, J=7.0 Hz). LCMS: ret. time: 10.42 min.; purity: 97%; MS (m/e):463 (MH⁺).

7.3.10815-Fluoro-N2-(indazoline-6-yl)-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine(R935363)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-trifluoromethoxyphenyl)-4-pyrimidineamine and6-aminoindazoline were reacted to give5-fluoro-N2-(indazoline-6-yl)-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 12.72 (s, 1H), 9.60 (s, 1H), 9.42 (s, 1H), 8.21 (d,1H, J=3.5 Hz), 8.06 (br s, 2H), 7.89 (s, 1H), 7.83 (s, 1H), 7.57 (d, 1H,J=8.8 Hz), 7.42 (t, 1H, J=8.2 Hz), 7.27 (d, 1H, J=8.8 Hz), 7.00 (d, 1H,J=8.2 Hz). LCMS: ret. time: 12.17 min.; purity: 97%; MS (m/e): 405(MH⁺).

7.3.1082 5-Fluoro-N2-(indazoline-5-yl)-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine (R935364)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-trifluoromethoxyphenyl)-4-pyrimidineamime and5-aminoindazoline were reacted to give5-fluoro-N2-(indazoline-5-yl)-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 12.85 (s, 1H), 9.54 (s, 1H), 9.23 (s, 1H), 8.15 (d,1H, J=3.5 Hz), 8.05 (s, 1H), 7.93 (d, 1H, J=8.2 Hz), 7.89 (s, 1H), 7.78(s, 1H), 7.48-7.35 (m, 3H), 7.01 (d, 1H, J=8.2 Hz). LCMS: ret. time:10.44 min.; purity: 98%; MS (m/e): 405 (MH⁺).

7.3.1083N4-(4-Chlorophenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine(R935365)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(4-chlorophenyl)-5-fluoro 4-pyrimidineamime and5-aminoindazoline were reacted to giveN4-(4-chlorophenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 12.85 (s, 1H), 9.43 (s, 1H), 9.19 (s, 1H), 8.11 (d,1H, J=3.5 Hz), 8.08 (s, 1H), 7.87 (s, 1H), 7.82 (dd, 2H, J=3.0 and 8.8Hz), 7.42 (dd, 2H, J=3.0 and 8.8 Hz), 7.31 (d, 2H, J=8.8 Hz). LCMS: ret.time: 9.07 min.; purity: 91%; MS (m/e): 355 (MH⁺).

7.3.1084N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine(R935366)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamimeand 5-aminoindazoline were reacted to giveN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 12.90 (s, 1H), 9.45 (s, 1H), 9.27 (s, 1H), 8.15 (d,1H, J=3.5 Hz), 8.11 (t, 1H, J=3.0 Hz), 8.02 (s, 1H), 7.87 (s, 1H), 7.84(d, 1H, J=8.8 Hz), 7.47 (d, 2H, J=8.8 Hz), 7.44 (d, 1H, J=8.8 Hz). LCMS:ret. time: 11.65 min.; purity: 98%; MS (m/e): 439 (MH⁺).

7.3.10855-Fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (R935367)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamineand 3, 4,5-trimethoxyaniline were reacted by microwave heating at 180°C. Upon concentration of the ethanol and addition of 2N HCl provided5-fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine as fine flakes of the solid.¹H NMR (DMSO-d₆): δ 9.59 (s, 1H), 9.25 (s, 1H), 8.09 (d, 1H, J=3.5 Hz),8.01 (dd, 2H, J=5.3 and 1.2 Hz), 7.39 (dd, 2H, J=3.1 and 8.8 Hz),7.60-7.54 (m, 3H), 7.03 (d, 2H, J=8.8 Hz), 6.94 (d, 2H, J=3.1 Hz), 5.57(s, 2H), 3.59 (s, 6H), 3.57 (s, 3H). LCMS: ret. time: 13.00 min.;purity: 97%; MS (m/e): 547 (MH⁺).

7.3.1086N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine(R935368)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamimeand 6-aminoindazoline were reacted to giveN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 12.73 (s, 1H), 9.67 (s, 1H), 9.46 (s, 1H), 8.21 (d,1H, J=3.5 Hz), 8.17 (app d, 1H, J=8.8 Hz), 8.04 (br s, 1H), 7.97 (dt,1H, J=2.4 and 9.3 Hz), 7.89 (s, 1H), 7.58 (d, 1H, J=8.8 Hz), 7.47 (d,1H, J=9.3 Hz), 7.27 (dd, 1H, J=1.7 and 8.8 Hz). LCMS: ret. time: 13.08min.; purity: 96%; MS (m/e): 439 (MH⁺).

7.3.1087N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]indazoline-5-yl]-2,4-pyrimidinediamine(R935369)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3-chloro-4-trifluoromethoxyphenyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provideN4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.62 (s, 1H), 9.29 (s, 1H), 8.17 (d, 1H, J=3.5 Hz),8.11 (t, 1H, J=2.4 Hz), 8.02 (app s, 1H), 7.88-7.82 (m, 3H), 7.53 (d,1H, J=9.3 Hz), 7.47 (d, 2H, J=8.8 Hz), 4.52 (t, 2H, J=7.0 Hz), 2.48 (t,2H, J=7.0 Hz), 2.48 (d, 3H, J=4.7 Hz). LCMS: ret. time: 10.51 min.;purity: 99%; MS (m/e): 524 (MH⁺).

7.3.1088N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine(R935370)

In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-(3-chloro-4-trifluoromethoxyphenyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediaminewas reacted with DIBAL-H to produceN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.62 (s, 1H), 9.28 (s, 1H), 8.17 (d, 1H, J=3.5 Hz),8.11 (s, 1H), 8.02 (s, 1H), 7.85 (s, 2H), 7.53 (t, 2H, J=8.8 Hz), 7.46(t, 1H, J=8.8 Hz), 4.56 (t, 1H, J=5.8 Hz), 4.38 (t, 2H, J=6.4 Hz), 3.35(dd, 2H, J=5.8 and 6.4 Hz), 1.93 (q, 2H, J=6.4 Hz). LCMS: ret. time:11.33 min.; purity: 99%; MS (m/e): 497 (MH⁺).

7.3.1089 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine(R935371)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-dichlorophenyl)-5-fluoro 4-pyrimidineamime and5-aminoindazoline were reacted to give N4-(3,4-dichlorophenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.90 (s, 1H), 9.60 (s, 1H), 8.20 (d, 1H, J=4.2 Hz),8.06 (t, 1H, J=2.3 Hz), 7.92 (s, 2H), 7.73 (d, 1H, J=8.8 Hz), 7.51-7.40(m, 3H). LCMS: ret. time: 9.83 min.; purity: 98%; MS (m/e): 390 (MH⁺).

7.3.1090 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine(R935372)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-dichlorophenyl)-5-fluoro 4-pyrimidineamine and6-aminoindazoline were reacted to give N4-(3,4-dichlorophenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 12.82 (s, 1H), 9.63 (s, 1H), 9.48 (s, 1H), 8.22 (d,1H, J=4.3 Hz), 8.15 (t, 1H, J=2.3 Hz), 8.02 (s, 1H), 7.92-7.90 (m, 2H),7.59 (d, 1H, J=8.8 Hz), 7.52 (d, 1H, J=8.8 Hz), 7.26 (dd, 1H, J=1.7 and8.8 Hz). LCMS: ret. time: 11.73 min.; purity: 99%; MS (m/e): 390 (MH⁺).

7.3.1091 N4-(3,4-Difluoromethylendioxyphenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine(R935373)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and5-aminoindazoline were reacted to give N4-(3,4-difluoromethylendioxyphenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.40 (s, 1H), 10.11 (s, 1H), 8.25 (d, 1H, J=4.5Hz), 7.95 (s, 1H), 7.89 (app s, 2H), 7.49 (d, 1H, J=8.8 Hz), 7.37 (appd, 3H, J=8.2 Hz). LCMS: ret. time: 8.56 min.; purity: 99%; MS (m/e): 401(MH⁺).

7.3.1092 N4-(3,4-Difluoromethylendioxyphenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine(R935374)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and6-aminoindazoline were reacted to give N4-(3,4-difluoromethylendioxyphenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.53 (s, 1H), 9.52 (s, 1H), 8.21 (d, 1H, J=4.5 Hz),8.10 (s, 1H), 8.01 (s, 1H), 7.92 (s, 1H), 7.59 (d, 1H, J=8.8 Hz), 7.48(dt, 1H, J=2.3 and 8.8 Hz), 7.34 (d, 1H, J=8.2 Hz), 7.21 (dd, 1H, J=2.3and 8.8 Hz). LCMS: ret. time: 11.29 min.; purity: 90%; MS (m/e): 401(MH⁺).

7.3.1093N4-(6-Chloro-3-pyridyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine(R935375)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(6-chloro-3-pyridyl)-5-fluoro-4-pyrimidineamine and5-amino-1-methylindazoline were reacted to giveN4-(6-chloro-3-pyridyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.96 (s, 1H), 9.58 (s, 1H), 8.86 (s, 1H), 8.25 (dt,1H, J=3.9 and 8.8 Hz), 8.20 (d, 1H, J=4.1 Hz), 8.04 (s, 1H), 7.55 (d,1H, J=8.8 Hz), 7.44 (d, 2H, J=8.8 Hz), 4.00 (s, 3H). LCMS: ret. time:8.95 min.; purity: 100%; MS (m/e): 370 (MH⁺).

7.3.1094N4-(6-Chloro-3-pyridyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine(R935376)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(6-chloro-3-pyridyl)-5-fluoro-4-pyrimidineamine and5-aminoindazoline were reacted to giveN4-(6-chloro-3-pyridyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.78 (s, 1H), 9.41 (s, 1H), 8.88 (s, 1H), 8.24 (d,1H, J=8.2 Hz), 8.18 (d, 1H, J=3.5 Hz), 8.06 (s, 1H), 7.92 (s, 1H), 7.42(app s, 3H). LCMS: ret. time: 7.87 min.; purity: 90%; MS (m/e): 356(MH⁺).

7.3.1095N4-(6-Chloro-3-pyridyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine(R935377)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(6-chloro-3-pyridyl)-5-fluoro-4-pyrimidineamine and5-amino-1-(2-ethoxycarbonylethyl)indazoline were reacted to giveN4-(6-chloro-3-pyridyl-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 10.37 (s, 1H), 10.04 (s, 1H), 8.78 (s, 1H), 8.28 (d,1H, J=4.8 Hz), 8.20 (dt, 1H, J=2.8 and 8.8 Hz), 7.96 (s, 1H), 7.92 (s,1H), 7.65 (d, 1H, J=8.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.41 (d, 1H, J=8.8Hz), 4.59 (t, 2H, J=6.0 Hz), 3.97 (qt, 2H, J=7.0 Hz), 2.90 (t, 2H, J=6.4Hz), 1.06 (t, 3H, J=7.0 Hz). LCMS: ret. time: 10.87 min.; purity: 94%;MS (m/e): 456 (MH⁺).

7.3.1096N4-(6-Chloro-3-pyridyl)-5-fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]indazoline-5-yl]-2,4-pyrimidinediamine(R935378)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(6-chloro-3-pyridyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provideN4-(6-Chloro-3-pyridyl)-5-fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.67 (s, 1H), 9.31 (s, 1H), 8.88 (s, 1H), 8.27 (dt,1H, J=3.0 and 8.8 Hz), 8.17 (d, 1H, J=3.5 Hz), 8.08 (s, 1H), 7.88 (s,1H), 7.83 (q, 1H, J=5.3 Hz), 7.53 (d, 1H, J=8.8 Hz), 7.45 (d, 1H, J=8.8Hz), 4.53 (t, 2H, J=7.0 Hz), 2.63 (t, 2H, J=7.0 Hz), 2.49 (d, 3H, J=5.3Hz). LCMS: ret. time: 7.62 min.; purity: 89%; MS (m/e): 441 (MH⁺).

7.3.1097N4-(6-Chloro-3-pyridyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine(R935379)

In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-(6-chloro-3-pyridyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediaminewas reacted with DIBAL-H to produceN4-(6-chloro-3-pyridyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): LCMS: ret. time: 8.02 min.; purity: 98%; MS (m/e): 414(MH⁺).

7.3.1098N4-(2,6-Dimethoxy-3-pyridyl)-5-fluoro-N2-[1-methylindazoline-5-yl]-2,4-pyrimidinediamine(R935380)

In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(2,6-dimethoxy-3-pyridyl)-6-5-fluoro-4-pyrimidineamine and1-methyl-5-aminoindazoline were reacted to giveN4-(2,6-dimethoxy-3-pyridyl)-5-fluoro-N2-[1-methylindazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 9.08 (s, 1H), 8.68 (s, 1H), 8.01 (d, 1H, J=4.1 Hz),7.96 (s, 1H), 7.76 (dd, 1H, J=4.1 and 8.8 Hz), 7.65 (s, 1H), 7.37 (d,1H, J=8.8 Hz), 7.34 (d, 1H, J=8.2 Hz), 6.46 (d, 1H, J=8.2 Hz), 3.94 (s,3H), 3.91 (s, 3H), 3.83 (s, 3H). LCMS: ret. time: 9.57 min.; purity:92%; MS (m/e): 396 (MH⁺).

7.3.1099 Additional 2,4-Pyrimidinediamine

Compounds R008951, R008952, R008953, R008955, R008956, R008958, R070153and R070790 (structures provided below) were purchased from ContactServices. Additional compounds whose structures are provided below weresynthesized using methods similar to those described in the previousexamples.

7.3.1100 Synthesis of Intermediates, 2,4-Pyrimidinediamines and2,4,6-Pyrimidinetriamines According to Schemes VIII and IX

A variety of intermediates and 2,4-pyrimidinediamine compounds weresynthesized according to Schemes VIII and IX. Scheme VIII is exemplifiedby the reaction of 2,4,6-trichloropyrimidine with 3-hydroxyaniline toform a mixture of three compounds, which were separated and purified bychromotography. Scheme IX is exemplified by the reaction of2,4,5,6-tetrachloridepyrimidine with 3,4-ethylenedioxyaniline to form amixture of three compounds, which were separated and purified bychromotography.

7.3.1101 Reaction of 2,4,6-trichloropyrimidine with 3-hydroxyaniline4,6-Dichloro-N2-(3-hydroxyphenyl)-2-pyrimidineamine (R926407)N2,N4-Bis(3-hydroxyphenyl)-6-chloro-2,4-pyrimidinediamine (R926408) andN2,N4,N6-Tris(3-hydroxyphenyl)-2,4,6-pyrimidinetriamine (R926409)

A mixture of 2,4,6-trichloroaniline (0.183 g, 1 mmol) and3-hydroxyaniline (0.327 g, 3 mmol) in 5 mL MeOH was heated at 100° C. ina sealed vial for 24 h. The reaction mixture was diluted with H₂O,acidified with 2N HCl and extracted with EtOAc (3×50 mL). Upon removalof solvent the residue was purified by chromatography (as well aspreparative TLC) to afford three products, mainly the mono-SNAr,4,6-dichloro-N2-(3-hydroxyphenyl)-2-pyrimidineamine (R926407): ¹H NMR(CDCl₃): δ 7.16 (t, 1H, J=8.1 Hz), 6.78 (m, 2H), 6.64 (dd, 1H, J=1.2 and8.1 Hz), 6.58 (s, 1H); LCMS: ret. time: 25.08 min.; purity: 99%; MS(m/e): 256 (M⁺); bis-SNAr product,N2,N4-bis(3-hydroxyphenyl)-6-chloro-2,4-pyrimidinediamine (R926408), ¹HNMR (CD₃OD): δ 7.21 (m, 1H), 7.14-7.03 (m, 5H), 6.50 (m, 1H), 6.44 (m,1H), 6.16 (s, 1H); LCMS: ret. time: 25.14 min.; purity: 99%; MS (m/e):329 (M⁺); and tris-SNAr product,N2,N4,N6-tris(3-hydroxyphenyl)-2,4,6-pyrimidinetriamine (R926409), ¹HNMR (CD₃OD): δ 7.29 (m, 1H), 7.12-7.05 (m, 5H), 7.02 (m, 2H), 6.88 (dd,2H, J=1.2 and 8.1 Hz), 6.46 (dd, 1H, J=1.5 and 8.1 Hz), 6.41 (dt, 1H);LCMS: ret. time: 20.49 min.; purity: 94%; MS (m/e): 402 (MH⁺).

7.3.1102N2,N4-Bis(4-methoxycarbonylmethyleneoxyphenyl)-6-chloro-2,4-pyrimidinediamine(R926411)

In like manner to the reaction of 2,4,6-trichloropyrimidine with3-hydroxyaniline, the reaction of 2,4,6-trichloropyrimidine with methyl4-aminophenoxyacetate gaveN2,N4-bis(4-methoxycarbonylmethyleneoxyphenyl)-6-chloro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.65 (bs, 1H), 7.40 (bd, 4H), 6.82 (bd, 4H), 6.00 (s,1H), 6.62 (bs, 4H), 3.78 (bs, 6H); LCMS: ret. time: 29.87 min.; purity:98%; MS (m/e): 473 (MH⁺).

7.3.1103 Reaction of 2,4,6-trichloropyrimidine with3,4-ethylenedioxyaniline4,6-Dichloro-N2-(3,4-ethylenedioxyphenyl)-2-pyrimidineamine (R926515)N2,N4-Bis(3,4-ethylenedioxyphenyl)-6-chloro-2,4-pyrimidinediamine(R926245)N2,N4,N6-Tris(3,4-ethylenedioxyphenyl)-2,4,6-pyrimidinetriamine(R926516)

A mixture of 2,4,6-trichloroaniline (1 mmol) and3,4-ethylenedioxyaniline (3 mmol) in 5 mL MeOH was heated at 100° C. ina sealed vial for 24 h. The reaction mixture was diluted with H₂O,acidified with 2N HCl and extracted with EtOAc (3×50 mL). Upon removalof solvent the residue was purified by chromatography (as well aspreparative TLC) to afford three products, mainly the Mono-SNAr product,4,6-dichloro-N2-(3,4-ethylenedioxyphenyl)-2-pyrimidineamine (R926515).¹H NMR (CD₃OD): δ 7.05 (s, 1H), 6.83 (m, 2H), 6.45 (bs, 1H), 4.20 (bs,4H); LCMS: ret. time: 29.75 min.; purity: 96%; MS (m/e): 298 (M⁺);Bis-SNAr product,N2,N4-bis(3,4-ethylenedioxyphenyl)-6-chloro-2,4-pyrimidinediamine(R926245): ¹H NMR (CDCl₃): δ 7.23 (d, 1H, J=3 Hz), 6.90-6.70 (m, 6H),6.02 (s, 1H), 4.26 (bs, 4H), 4.23 (m, 4H); LCMS: ret. time: 31.34 min.;purity: 95%; MS (m/e): 413 (MH⁺) and Tris-SNAr product,N2,N4,N6-tris(3,4-ethylenedioxyphenyl)-2,4,6-pyrimidinetriamine(R926516) ¹H NMR (CD₃OD): δ 7.16 (d, 1H, J=3 Hz), 7.05 (bd, 1H),6.99-6.90 (m, 3H), 6.80-6.70 (m, 4H), 6.03 (s, 1H), 4.22 (s, 4H), 4.20(s, 8H); LCMS: ret. time: 27.72 min.; purity: 61%; MS (m/e): 528 (M⁺).

7.3.1104 Reaction of 2,4,6-trichloropyrimidine withethyl-4-aminophenoxyacetate4,6-Dichloro-N2-(4-ethoxycarbonylmethyl)-4,6-dichloro-2-pyrimidineamine(R926549) 2,6-Dichloro-N4-(ethoxycarbonylmethyl)-4-pyrimidineamine(R926550)

A mixture of 2,4,6-trichloroaniline (1 mmol) and ethyl 2-aminoacetate (3mmol) in 5 mL MeOH was heated at 100° C. in a sealed vial for 24 h. Thereaction mixture was diluted with H₂O, acidified with 2N HCl andextracted with EtOAc (3×50 mL). Upon removal of solvent the residue waspurified by chromatography (as well as preparative TLC) to afford threeproducts, mainly the mono-SNAr product,4,6-dichloro-N2-(4-ethoxycarbonylmethyl)-4,6-dichloro-2-pyrimidineamine(R926549). ¹H NMR (CDCl₃): δ 6.67 (s, 1H), 5.85 (bs, 1H), 4.23 (q, 2H,J=7.2 Hz), 4.19 (s, 2H), 1.29 (t, 3H, J=7.2 Hz); LCMS: ret. time: 26.18min.; purity: 100%; MS (m/e): 250 (MH⁺); and Mono-SNAr product,2,6-dichloro-N4-(ethoxycarbonylmethyl)-4-pyrimidineamine (R926550): ¹HNMR (CDCl₃): δ 6.37 (bs, 1H), 4.28 (q, 2H, J=6.9 Hz), 4.19 (bs, 2H),1.31 (t, 3H, J=7.2 Hz)

7.3.11056-Chloro-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(methoxycarbonylmethyl)-2,4-pyrimidinediamine(R926555)

In like manner to the preparation of 4-[N-(L)-phenylalanine ethylester]-N2-(3-hydroxyphenyl)-5-ethoxycarbonyl-2-pyrimidineamine, thereaction of ethyl 4-aminophenoxyacetate with methyl 2-aminoacetate gave6-chloro-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(methoxycarbonylmethyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.40 (d, 2H, J=8.7 Hz), 6.86 (d, 2H, J=9.3 Hz), 5.97(s, 1H), 4.64 (s, 2H), 4.26 (q, 2H, J=7.2 Hz), 4.14 (q, 2H, J=6.9 Hz),4.05 9s, 2H), 1.25 (m, 6H); LCMS: ret. time: 26.21 min.; purity: 93%; MS(m/e): 409 (MH⁺).

7.3.1106 Reaction of 3,4-ethylenedioxyaniline with2,4,5,6-tetrachloropyrimidineN4-(3,4-Ethylenedioxyphenyl)-2,5,6-trichloro-4-pyrimidineamine (R926466)N2,N4-Bis(3,4-ethylenedioxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine(R926467) andN4,N6-Bis(3,4-ethylenedioxyphenyl)-2,5-dichloro-4,6-pyrimidinediamine(R926468)

A mixture of 3,4-ethylenedioxyaniline (0.775 g, 5 mmol) and2,4,5,6-tetrachloropyrimidine (0.434 g, 2 mmol) in the presence of DIPEA(1.043 mL, 6 mmol) in EtOAc (10 mL) was heated at 80° C. for 3 days. Thereaction was diluted with water (50 mL), acidified (2N HCl) andextracted with EtOAc (3×50 mL). The residue obtained after removal ofsolvent was chromatographed using 5-30% EtOAc/hexanes to obtain threeproducts viz.N4-(3,4-Ethylenedioxyphenyl)-2,5,6-trichloro-4-pyrimidineamine(R926466): ¹H NMR (CDCl₃): δ 7.18 (d, 1H, J=2.7 Hz), 6.92 (dd, 1H, J=2.1and 8.7 Hz), 6.87 (d, 1H, J=9 Hz); LCMS: ret. time: 33.53 min.; purity:100%; MS (m/e): 292 (MH⁺);N2,N4-Bis(3,4-ethylenedioxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine(R926467): ¹H NMR (CDCl₃): δ 7.11 (d, 1H, J=2.4 Hz), 7.06 (d, 1H, J=2.1Hz), 7.04 (s, 1H0, 6.94 (m, 2H), 6.84 (d, 1H, J=8.1 Hz), 6.76 (bd, 2H,J=8.7 Hz), 4.27 (bs, 4H), 4.24 (bs, 1H); LCMS: ret. time: 26.54 min.;purity: 87%; MS (m/e): 364 (MH⁺); andN4,N6-Bis(3,4-ethylenedioxyphenyl)-2, 5-dichloro-4,6-pyrimidinediamine(R926468): ¹H NMR (CDCl₃): δ 7.07 (t, 1H, J=2.4 Hz), 6.99 (s, 2H), 6.83(dd, 2H, J=2.4 and 8.7 Hz), 6.75 (dd, 2H, J=1.8 and 9 Hz), 4.19 (bs,4H); LCMS: ret. time: 34.70 min.; purity: 99%; MS (m/e): 365 (MH⁺).

7.3.1107 Reaction of 2,4,5,6-tetrachloropyrimidine withethyl-4-aminophenoxyacetateN4-(4-Ethoxycarbonylmethyleneoxyphenyl)-2,5,6-trichloro-4-pyrimidineamine(R926568)N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine(R926569)N2,N5-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-2,5-pyrimidinediamine(R926570)

In like manner to the reaction of 2,4,6-trichloropyrimidine with3,4-ethylenedioxyaniline, the reaction of 2,4,5,6-tetrachloropyrimidinewith ethyl 4-aminophenoxyacetate gave a mixture of mono-SNAr product,N4-(4-ethoxycarbonylmethyleneoxyphenyl)-2,5,6-trichloro-4-pyrimidineamine (R926568): ¹H NMR(CDCl₃): δ 7.46 (dd, 2H, J=2.4 and 6.9 Hz), 7.3 (s, 1H), 6.95 (dd, 2H,J=2.4 and 6.9 Hz), 4.63 (s, 2H), 4.28 (q, 2H, J=7.2 Hz), 1.30 (t, 3H,J=7.2 Hz); LCMS: ret. time: 30.62 min.; purity: 99%; MS (m/e): 378(MH⁺); Bis-SNAr product, N2,N4-bis((4-ethoxycarbonylmethyleneoxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine (R926569): ¹H NMR (CDCl₃):δ 7.42 (d, 2H, J=9 Hz), 7.35 (d, 2H, J=8.7 Hz), 6.90 (d, 2H, J=9 Hz),6.83 (d, 2H, J=8.7 Hz), 4.67 (s, 2H), 4.60 (s, 2H), 4.28 (2q, 4H, J=4.8Hz), 1.31 (2t, 6H, J=6.3 Hz); LCMS: ret. time: 33.09 min.; purity: 85%;MS (m/e): 537 (MH⁺) and Bis-SNAr product,N2,N5-bis((4-ethoxycarbonylmethyleneoxyphenyl)-2,5-pyrimidinediamine(R926570): ¹H NMR (CDCl₃): δ 7.45 (d, 4H, J=8.7 Hz), 6.92 (d, 4H, J=9Hz), 6.85 (s, 1H), 4.61 (s, 4H), 4.26 (q, 4H, J=6.9 Hz), 1.30 (t, 6H,J=7.2 Hz); LCMS: ret. time: 31.66 min.; purity: 97%; MS (m/e): 535(MH⁺).

7.3.1108 Reaction of 2,4,5,6-tetrachloropyrimidine withtert-Butyl-4-aminophenoxyacetate,N4-(4-tert-Butoxyoxycarbonylmethyleneoxyphenyl)-2,5,6-trichloro-4-pyrimidineamine(R926575),N2,N4-Bis(4-tert-butoxyoxycarbonylmethyleneoxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine(R926576) andN4,N6-Bis(4-tert-butoxyoxycarbonylmethyleneoxyphenyl)-2,5-dichloro-4,6-pyrimidinediamine(R926577)

In like manner to the reaction of 2,4,6-trichloropyrimidine with3,4-ethylenedioxyaniline, the reaction of 2,4,5,6-tetrachloropyrimidinewith tert-butyl-4-aminophenoxyacetate gave a mixture of mono-SNArproduct, N4-(4-tert-butoxyoxycarbonylmethyleneoxyphenyl)-2,5,6-trichloro-4-pyrimidineamine (R926575): ¹H NMR(CDCl₃): δ 7.45 (dd, 2H, J=2.4 and 7.2 Hz), 6.93 (dd, 2H, J=2.4 and 7.2Hz), 4.52 (s, 2H); LCMS: ret. time: 32.56 min.; purity: 100%; MS (m/e):402 (MH⁺); Bis-SNAr product,N2,N4-bis(4-tert-butoxyoxycarbonylmethyleneoxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine(R926576): ¹H NMR (CDCl₃): δ 7.42 (d, 2H, J=9 Hz), 7.35 (d, 2H, 9.3 Hz),7.08 (s, 1H), 6.90 (d, 2H, J=9.3 Hz), 6.82 (d, 2H, J=8.7 Hz), 4.53 (s,2H), 4.49 (s, 2H), 1.50 (s, 9H), 1.49 (s, 9H); LCMS: ret. time: 36.04min.; purity: 92%; MS (m/e): 591 (MH⁺) and Bis-SNAr product,N4,N6-bis(4-tert-butoxyoxycarbonylmethyleneoxyphenyl)-2,5-dichloro-4,6-pyrimidinediamine(R926577): ¹H NMR (CDCl₃): δ 7.43 (d, 4H, J=8.7 Hz), 6.90 (dd, 4H, J=9.3Hz), 4.50 (s, 2H), 1.49 (s, 18H); LCMS: ret. time: 35.31 min.; purity:100%; MS (m/e): 591 (MH⁺).

7.3.1109 Reaction of 2,4,5,6-tetrachloropyrimidine with3-hydroxyaniline, N4-(3-Hydroxyphenyl)-2,5,6-trichloro-4-pyrimidineamine(R926590), N2,N4-Bis(3-hydroxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine(R926591) andN4,N6-Bis(3-hydroxyphenyl)-2,5-dichloro-4,6-pyrimidinediamine (R926592)

In like manner to the reaction of 2,4,6-trichloropyrimidine with3,4-ethylenedioxyaniline, the reaction of 2,4,5,6-tetrachloropyrimidinewith tert-butyl-4-aminophenoxyacetate gave a mixture of mono-SNArproduct, N4-(3-hydroxyphenyl)-2,5,6-trichloro-4-pyrimidineamine(R926590): ¹H NMR (CDCl₃): δ 7.38 (bs, 1H), 7.32 (t, 1H, J=2.4 Hz), 7.22(s, 1H), 7.01 (dd, 1H, J=1.2 and 8.1 Hz), 6.68 (dd, 1H, J=1.8 and 8.1Hz); LCMS: ret. time: 26.09 min.; purity: 99%; MS (m/e): 292 (MH⁺);Bis-SNAr product,N2,N4-bis(3-hydroxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine (R926591):¹H NMR (CDCl₃): δ 7.45 (s, 1H), 7.30 (t, 1H, J=2.4 Hz), 7.18 (t, 1H,J=2.4 Hz), 7.07 (t, 1H, j=6.6 Hz), 6.98 (t, 1H, J=8.1 Hz), 6.75 (m, 2H),6.54 (dd, 1H, J=2.4 and 8.1 Hz); LCMS: ret. time: 26.54 min.; purity:87%; MS (m/e): 364 (MH⁺); and Bis-SNAr product,N4,N6-bis(3-hydroxyphenyl)-2,5-dichloro-4,6-pyrimidinediamine (R926592):¹H NMR (CDCl₃): δ 7.34 (t, 2H, j=2.4 Hz), 7.21 (t, 2H, J=7.5 Hz), 6.98(m, 4H), 6.60 (m, 2H); LCMS: ret. time: 25.38 min.; purity: 73%; MS(m/e): 364 (MH⁺).

7.3.1110N2,N4-Bis(3-hydroxyphenyl)-5-chloro-6-thiomethyl-2,4-pyrimidinediamine(R926595)

The reaction of N2N4-bis(3-hydroxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine (18 mg, 0.05mmol) with sodium thiomethoxide (10 mg, 0.15 mmol) in absolute EtOH (1mL) was heated at 80° C. for 3 days, diluted with H₂O, extracted withEtOAc (3×10 mL), and solvent was evaporated to obtain the N2N4-bis(3-hydroxyphenyl)-5-chloro-6-thiomethyl-2,4-pyrimidinediamine(R926595). ¹H NMR (CD₃OD): δ 7.40-7.2 (m, 2H), 7.20-6.80 (m, 3H), 6.67(m, 1H), 6.45-6.30 (m, 2H), 2.4 (s, 3H); LCMS: ret. time: 27.78 min.;purity: 80%; MS (m/e): 376 (MH⁺).

7.3.1111N2,N4-Bis(3,4-ethyelenedioxyphenyl)-5-chloro-6-thiomethyl-2,4-pyrimidinediamine(R926475)

In like manner to the preparation of N2N4-bis(3-hydroxyphenyl)-5-chloro-6-thiomethyl-2,4-pyrimidinediamine(R926595), the reaction ofN2,N4-bis(3,4-ethyelenedioxyphenyl)-5,6-dichloro-2,4-pyrimidinediaminegaveN2,N4-bis(3,4-ethyelenedioxyphenyl)-5-chloro-6-thiomethyl-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.10 (bd, 2H), 7.00-6.00 (m, 4H), 4.23 (s, 4H), 4.10(s, 4H), 2.60 (s, 3H); LCMS: ret. time: 36.14 min; purity: 100%; MS(m/e): 459 (MH⁺).

7.3.1112 6-Chloro N4-(3-hydroxyphenyl)-4-pyrimidineamine (R926530)

The reaction of 4,6-dichloropyrimidine with excess 3-hydroxyaniline inMeOH at 80 0° C. for 24 h followed by dilution with water andacidification gave the crude product which was purified by silica gelcolumn chromatography to obtain 6-chloroN4-(3-hydroxyphenyl)-4-pyrimidineamine. ¹H NMR (CD₃OD): δ 8.36 (d, 1H,J=1.2 Hz), 7.15 (t, 1H, J=8.4 Hz), 6.93 (dd, 1.2 and 8.1 Hz), 6.74 (d,1H, J=1.2 Hz), 6.55 (dd, 1.8 and 8.1 Hz); LCMS (m/e): ret. time: 19.75min.; purity: 99%; MS (m/e): 222 (MH⁺).

7.3.1113N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine(R925784)

A mixture ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine (20 mg,0.044 mmol) and phenylboronic acid (6.9 mg, 0.057 mmol) in DME (1 mL)was prepared in a sealed tube and purged with N₂.Tetrakis(triphenylphosphine) palladium(0) (0.002 mmol) was added, andthe reaction tube sealed and heated at 80° C. overnight. After cooling,the reaction mixture was diluted with EtOAc, washed with 1N NaOH andbrine, dried (MgSO₄), and concentrated. The residue was purified bypreparative TLC (40% EtOAc/hexanes) to affordN2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine. ¹HNMR (CD₃OD): δ 7.77 (s, 1H), 7.52-7.36 (m, 5H), 7.10 (d, 1H, J=2.4 Hz),7.05 (d, 1H, J=2.4 Hz), 6.93 (dd, 1H, J=2.4 and 8.7 Hz), 6.87 (dd, 1H,J=2.4 and 8.7 Hz), 6.73 (d, 1H, J=8.7 Hz), 6.69 (d, 1H, J=8.7 Hz),4.23-4.20 (m, 8H); LCMS: ret. time: 25.38 min.; purity: 100%; MS (m/e):455 (MH⁺).

7.3.1114N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-(2-furanyl)-2,4-pyrimidinediamine(R925785)

In a manner similar to the preparation ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine,N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine andfuran-2-boronic acid were reacted to yieldN2,N4-bis(3,4-ethylenedioxyphenyl)-5-(2-furanyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 8.13 (s, 1H), 7.61 (d, 1H, J=1.8 Hz), 7.12 (d, 1H,J=2.4 Hz), 7.08 (d, 1H, J=2.4 Hz), 6.93 (td, 2H, J=2.4 and 8.7 Hz), 6.78(d, 1H, J=8.7 Hz), 6.68 (d, 1H, J=8.7 Hz), 6.58 (d, 1H, J=2.4 Hz), 6.54(dd, 1H, J=1.8 and 3.6), 4.24 (s, 4H), 4.20 (bs, 4H); LCMS: ret. time:15.03 min.; purity: 88%; MS (m/e): 445 (MH⁺).

7.3.1115N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-(4-chlorophenyl)-2,4-pyrimidinediamine(R925786)

In a manner similar to the preparation ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine,N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine and4-chlorophenylboronic acid were reacted to yieldN2,N4-bis(3,4-ethylenedioxyphenyl)-5-(4-chlorophenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 8.99 (bs, 1H), 8.05 (bs, 1H), 7.85 (s, 1H),7.50-7.42 (m, 4H), 7.23 (bs, 1H), 7.10 (dd, 1H, J=2.4 and 8.7 Hz), 7.06(t, 1H, J=2.4 Hz), 7.00-6.94 (m, 1H), 6.73 (d, 1H, J=8.7 Hz), 6.63 (d,1H, J=8.7 Hz); LCMS: ret. time: 16.12 min.; purity: 86%; MS (m/e): 490(MH⁺).

7.3.1116N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-(3-chlorophenyl)-2,4-pyrimidinediamine(R925787)

In a manner similar to the preparation ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine,N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine and3-chlorophenylboronic acid were reacted to yieldN2,N4-bis(3,4-ethylenedioxyphenyl)-5-(3-chlorophenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.77 (s, 1H), 7.45-7.41 (m, 2H), 7.38-7.33 (m, 2H),7.09 (d, 1H, J=2.4 Hz), 7.01 (d, 1H, J=2.4 Hz), 6.92 (dd, 1H, J=2.4 and9.0 Hz), 6.86 (dd, 1H, J=2.4 and 8.7 Hz), 6.74 (d, 1H, J=8.7 Hz), 6.67(d, 1H, J=8.7 Hz), 4.21 (s, 4H), 4.19 (s, 4H); LCMS: ret. time: 27.18min.; purity: 95%; MS (m/e): 490 (MH⁺).

7.3.1117N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-(4-methoxycarbonylphenyl)-2,4-pyrimidinediamine(R925813)

In a manner similar to the preparation ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine,N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine and(4-methoxycarbonylphenyl)boronic acid were reacted to yieldN2,N4-bis(3,4-ethylenedioxyphenyl)-5-(4-methoxycarbonylphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 26.35 min.; purity: 90%; MS (m/e): 514 (MH⁺).

7.3.1118N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-(4-hydroxyphenyl)-2,4-pyrimidinediamine(R925816)

In a manner similar to the preparation ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine,N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine and4-hydroxyphenylboronic acid were reacted to yieldN2,N4-bis(3,4-ethylenedioxyphenyl)-5-(4-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 9.53 (s, 1H), 8.92 (s, 1H), 7.78 (s, 1H), 7.74 (bs,1H), 7.24 (bs, 1H), 7.22 (d, 2H, J=8.7 Hz), 7.12-7.09 (m, 2H), 6.97 (dt,1H, J=2.4 and 8.7 Hz), 6.83 (d, 2H, J=8.4 Hz), 6.72 (d, 1H, J=8.1 Hz),6.62 (d, 1H, J=9.0 Hz), 4.19 (s, 4H), 4.17 (s, 4H); LCMS: ret. time:23.51 min.; purity: 95%; MS (m/e): 471 (MH⁺).

7.3.1119 N2,N4-Bis(3-hydroxyphenyl)-5-phenyl-2,4-pyrimidinediamine(R925783)

In a manner similar to the preparation ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine,N2,N4-bis(3-hydroxyphenyl)-5-bromo-2,4-pyrimidinediamine andphenylboronic acid were reacted to yieldN2,N4-bis(3-hydroxyphenyl)-5-phenyl-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ 7.85 (bs, 1H), 7.54-7.38 (m, 5H), 7.13-7.11 (m, 2H).7.10-7.04 (m, 3H), 6.97 (dt, 1H, J=1.8 and 8.1 Hz), 6.54 (ddd, 1H,J=1.9, 2.4, and 7.2 Hz), 6.44 (dt, 1H, J=1.8 and 6.0 Hz); LCMS: ret.time: 20.66 min.; purity: 96%; MS (m/e): 371 (MH⁺).

7.3.1120N2,N4-Bis(3-hydroxyphenyl)-5-(3,4-methylenedioxyphenyl)-2,4-pyrimidinediamine(R925788)

In a manner similar to the preparation ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine,N2,N4-bis(3-hydroxyphenyl)-5-bromo-2,4-pyrimidinediamine and3,4-methylenedioxyphenylboronic acid were reacted to yieldN2,N4-bis(3-hydroxyphenyl)-5-(3,4-methylenedioxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 7.82 (s, 1H), 7.13-7.06 (m, 3H), 7.04-7.01 (m, 2H),6.97 (dt, 1H, J=1.2 and 8.7 Hz), 6.94-6.88 (m, 3H), 6.52 (ddd, 1H,J=1.2, 2.4, and 6.9 Hz), 6.42 (dt, 1H, J=2.1 and 7.5 Hz), 6.01 (s, 2H);LCMS: ret. time: 21.11 min.; purity: 99%; MS (m/e): 415 (MH⁺).

7.3.1121N2,N4-Bis(3,4-ethylenedioxyphenyl)-6-phenyl-2,4-pyrimidinediamine(R925811)

In a manner similar to the preparation ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine,N2,N4-bis(3,4-ethylenedioxyphenyl)-6-chloro-2,4-pyrimidinediamine andphenylboronic acid were reacted to yieldN2,N4-bis(3,4-ethylenedioxyphenyl)-6-phenyl-2,4-pyrimidinediamine. ¹HNMR (CD₃OD): δ 7.97-7.92 (m, 2H), 7.46-7.43 (m, 3H), 7.35 (d, 1H, J=2.7Hz), 7.19 (d, 1H, J=2.4 Hz), 7.07-7.00 (m, 2H), 6.75 (t, 2H, J=8.7 Hz),6.50 (s, 1H), 4.24-4.19 (m, 8H); LCMS: ret. time: 26.68 min.; purity:97%; MS (m/e): 455 (MH⁺).

7.3.1122 N2,N4-Bis(3-hydroxyphenyl)-6-phenyl-2,4-pyrimidinediamine(R925812)

In a manner similar to the preparation ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine,N2,N4-bis(3-hydroxyphenyl)-6-chloro-2,4-pyrimidinediamine andphenylboronic acid were reacted to yieldN2,N4-bis(3-hydroxyphenyl)-6-phenyl-2,4-pyrimidinediamine. LCMS: ret.time: 22.13 min.; purity: 90%; MS (m/e): 371 (MH⁺).

7.3.1123N2-(3-Aminocarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926747)

The hydrolysis ofN2-(3-cyanomethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediaminegaveN2-(3-aminocarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 16.76 min.; purity: 93%; MS (m/e): 412 (MH⁺).

7.3.1124 N2,N4-Bis(3-sodiumphenoxy)-5-fluoro-2,4-pyrimidinediamine(R926461)

The reaction ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine with 2equivalents of sodium methoxide in methanol gave the requisite compound,N2,N4-bis(3-sodiumphenoxy)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR (D₂O):δ 7.65 (bd, 1H), 7.00-6.90 (m, 2H), 6.71 (m, 2H), 6.55 (dd, 1H, J=1.2and 6.3 Hz), 6.31 (bd, 1H, J=8.1 Hz), 6.23 (bd, 1H, J=8.7 Hz); ¹⁹F NMR(D₂O): −47016; LCMS: ret. time: 15.68 min.; purity: 99%; MS (m/e): 313(MH⁺).

7.3.11255-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1,4,5,6-tetrahydro-2-pyrimidyl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945169)

The reaction ofN2-(4-cyanomethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand HCl in ethanol, followed by 1,3-diaminopropane in methanol at 100°C. gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1,4,5,6-tetrahydro-2-pyrimidyl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ 2.05 (p, J=5.7 Hz, 2H), 3.49 (t, J=5.7 Hz, 4H), 4.84(s, 2H), 6.56 (ddd, J=2.1, 3.6 and 5.4 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H),7.11-7.13 (m, 2H), 7.21 (m, 1H), 7.55 (d, J=9.0 Hz, 2H), 7.87 (d, J=3.9Hz, 1H); ¹⁹F NMR (282 MHz, CD₃OD): δ −168.66; LCMS: ret. time: 12.77min.; purity: 97.61%; MS (m/e): 409.08 (MH⁺).

7.3.11265-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-[(4,4-dimethyl-3-oxazolin-2-yl)methyleneoxy]phenyl]-2,4-pyrimidinediamine(R926702)

N2-[4-(cyanomethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand 2-amino-2-methylpropanol were reacted to yield5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-[(4,4-dimethyl-3-oxazolin-2-yl)methyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 7.87 (d, 1H, J=3.6 Hz), 7.37 (t, 1H, J=2.4 Hz), 7.34(d, 2H, J=9.0 Hz), 7.14 (t, 1H, J=8.1 Hz), 6.94 (bs, 1H), 6.90 (d, 2H,J=9.0 Hz), 6.78 (dd, 1H, J=2.4 and 8.4 Hz), 6.74 (d, 1H, J=3.0 Hz), 6.62(ddd, 1H, J=1.2, 2.4, and 8.4 Hz), 4.67 (s, 2H), 4.02 (s, 2H), 1.25 (s,6H); ¹⁹F NMR (CDCl₃): −47399; LCMS: ret. time: 13.82 min.; purity: 98%;MS (m/e): 425 (M+2H).

7.3.1127N4-(3-Carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950290)

A mixture of equimolar amounts of2-chloro-N4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-4-aminopyridine and3-ethoxycarbonylmethyleneoxyaniline in MeOH in a pressure tube at 110°C. for 24 h or in EtOH using microwave at 175° C. for 10-20 min followedby aqueous work up gaveN4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 97.8%; MS (m/e): 443.20 (MH⁺).

7.3.1128N4-(3-Carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-carboxymethyleneoxyphenyl]-2,4-pyrimidinediamine(R950291)

The reaction ofN4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(0.1 g) and LiOH (10 equivalents) in MeOH:water (1:1, v/v) for 1 h atroom temperature followed by treatment with aqueous HCl gave the solid.The resulting solid was filtered, washed with water and dried to giveN4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-carboxymethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 91.5%; MS (m/e): 415.16 (MH⁺).

7.3.1129N4-(3-Methoxycarbonyl-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950293)

A solution ofN4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein dry MeOH was treated with a 4 M solution of HCl in dioxane. Themixture was stirred for 1 hour at 22° C., concentrated to dryness andpurified by flash chromatography on silica gel to giveN4-(3-methoxycarbonyl-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ 10.30 (s, 1H), 10.13 (s, 1H), 8.22(d, 1H, J=5.3 Hz), 7.96 (d, 1H, J=2.4 Hz), 7.71 (dd, J=2.4, 9.0 Hz, 1H),6.95-7.11 (m, 4H), 6.51 (m, 1H), 4.56 (s, 2H), 4.09 (q, J=7.2 Hz, 2H),3.72 (s, 3H), 1.14 (j, J=7.2 Hz, 3H); LCMS: purity: 96.8%; MS (m/e):457.25 (MH⁺).

7.3.1130N4-(4-Methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950294)

A mixture of equimolar amounts of2-chloro-N4-(4-methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-4-aminopyridineand 3-ethoxycarbonylmethyleneoxyaniline in EtOH using microwave at 175°C. for 10-20 min followed by aqueous work up gaveN4-(4-methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 92.1%; MS (m/e): 469.26 (MH⁺).

7.3.1131N4-(4-Methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-methoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950295)

A mixture of equimolar amounts of2-chloro-N4-(4-methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-4-aminopyridineand 3-ethoxycarbonylmethyleneoxyaniline in MeOH in a pressure tube at110° C. for 24 h followed by aqueous work up gaveN4-(4-methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-methoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 87.6%; MS (m/e): 455.26 (MH⁺).

7.3.1132N4-(4-Ethoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950296)

A solution ofN4-(4-ethoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein EtOH was treated with the HCl salt of methylamine. The mixture wasstirred for 4 hours at 100° C., concentrated to dryness and purified byflash chromatography on silica gel to giveN4-(4-ethoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 87.4%; MS (m/e): 468.29 (MH⁺).

7.3.1133N4-(4-Carboxyethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950344)

A mixture of equimolar amounts of2-chloro-N4-(4-carboxyethyleneoxyphenyl)-5-fluoro-4-aminopyridine and3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in a pressure tubeat 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20 minfollowed by aqueous work up gaveN4-(4-carboxyethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 97.8%; MS (m/e): 456.32 (MH⁺).

7.3.1134N4-(2,3-Dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950345)

A solution ofN4-(4-Methoxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein TfOH was heated for 2 hours at 100° C. Aqueous work up followed byflash chromatography on silica gel gaveN4-(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 92.2%; MS (m/e): 435.95 (MH⁺).

7.3.1135N4-(4-Methoxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950346)

A solution ofN4-(4-carboxyethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein dry MeOH was treated with a 4 M solution of HCl in dioxane. Themixture was stirred for 1 hour at 22° C., concentrated to dryness andpurified by flash chromatography on silica gel to giveN4-(4-methoxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 85.2%; MS (m/e): 468.01 (MH⁺).

7.3.1136N4-(4-Hydroxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950347)

The reaction ofN4-(4-methoxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand LiOH (10 equivalents) in MeOH:water (1:1, v/v) for 1 h at roomtemperature followed by treatment with aqueous HCl gave a pale yellowsolid. The resulting solid was filtered, washed with water and dried togiveN4-(4-hydroxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 94.7%; MS (m/e): 382.03 (MH⁺).

7.3.1137N4-(2,3-Dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950348)

A mixtureN4-(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand hydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN4-(2,3-dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 89.5%; MS (m/e): 451.00 (MH⁺).

7.3.1138N4-(4-Hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950349)

A solution ofN4-(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein dry MeOH was treated with a sodiumcyanoborohydride. The mixture wasstirred for 1 hour at 22° C., concentrated to dryness and purified byflash chromatography on silica gel to giveN4-(4-Hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ 9.19 (s, 1H), 9.09 (s, 1H), 8.03 (d,1H, J=2.4 Hz), 7.28-7.93 (m, 5H), 7.07 (t, 1H, J=7.2 Hz), 6.71 (d, 1H,J=7.2 Hz), 6.44 (dd, 1H, J=2.6, 7.2 Hz), 5.31 (d, 1H, J=5.1 Hz),4.14-4.59 (m, 3H), 4.30 (s, 2H), 2.63 (d, 3H, J=4.8 Hz), 1.82-2.03 (m,2H); LCMS: purity: 93.3%; MS (m/e): 440.15 (MH⁺).

7.3.1139N4-(2,3-Dihydro-4-O-methyloxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950356)

A mixtureN4-(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand methoxyamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN4-(2,3-dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 85.5%; MS (m/e): 465.10 (MH⁺).

7.3.1140N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950368)

A mixtureN4-(4-azido-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand Pd/C (10%) in MeOH was hydrogenated at 22° C. for 6 hours (40 psi).The mixture was filtered and concentrated to dryness to giveN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ 9.60 (s, 1H), 9.46 (s, 1H), 8.73 (bs,3H), 8.00-8.10 (m, 3H), 7.47 (s, 1H), 7.42 (m, 1H), 7.29 (d, 1H, J=7.2Hz), 7.11 (t, 1H, J=7.2 Hz), 6.82 (d, 1H, J 7.0 Hz), 6.46 (m, 1H),4.23-4.46 (m, 3H), 4.31 (s, 3H), 2.63 (d, 3H, J=4.8 Hz), 2.09-2.29 (m,2H); LCMS: purity: 97.6%; MS (m/e): 438.98 (MH⁺).

7.3.1141N4-(3-Methylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950371)

A mixture of equimolar amounts of2-chloro-N4-(3-methylcarbonylphenyl)-5-fluoro-4-aminopyridine and3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in a pressure tubeat 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20 minfollowed by aqueous work up gaveN4-(3-methylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ 10.16 (s, 1H), 9.82 (s, 1H), 8.24 (d,1H, J=2.4 Hz), 8.15 (s, 1H), 7.91-8.07 (m, 2H), 7.70 (d, 1H, J=7.0 Hz),7.49 (t, 1H, J=7.2 Hz), 7.08-7.21 (m, 3H), 6.56 (d, 1H, J=7.2 Hz), 4.30(s, 3H), 2.62 (d, 3H, J=4.8 Hz), 2.48 (s, 3H); LCMS: purity: 93.8%; MS(m/e): 410.50 (MH⁺).

7.3.1142N4-(3-Phenylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950372)

A mixture of equimolar amounts of2-chloro-N4-(3-phenylcarbonylphenyl)-5-fluoro-4-aminopyridine and3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in a pressure tubeat 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20 minfollowed by aqueous work up gaveN4-(3-phenylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 86.0%; MS (m/e): 472.50 (MH⁺).

7.3.1143N4-(3-Methylcarbonyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950373)

A mixtureN4-(3-methylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand hydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN4-(3-methylcarbonyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ 11.21 (s, 1H), 10.11 (s, 1H), 9.85(s, 1H), 6.54-8.23 (m, 9H), 4.32 (s, 2H), 2.63 (d, J=7.0 Hz, 3H), 2.47(s, 3H); LCMS: purity: 92.4%; MS (m/e): 425.28 (MH⁺).

7.3.1144N4-(3-Phenylcarbonyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950374)

A mixtureN4-(3-phenylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand hydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN4-(3-phenylcarbonyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ 11.63 (s, 1H), 10.30 (s, 1H), 9.85(s, 1H), 6.44-8.43 (m, 14H), 4.42 (s, 2H), 2.63 (d, J=7.0 Hz, 3H); LCMS:purity: 92.4%; MS (m/e): 487.31 (MH⁺).

7.3.1145N2,N4-Bis(3-methylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R950376)

A mixture of 2,4-dichloro-5-fluoropyridine and three equivalents of3-acetophenone in MeOH in a pressure tube at 110° C. for 24 h or in EtOHusing microwave at 175° C. for 10-20 min followed by aqueous work upgave N2,N4-bis(3-methylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine asa white solid. LCMS: purity: 93.1%; MS (m/e): 365.19 (MH⁺).

7.3.1146N2,N4-Bis(3-phenylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R950377)

A mixture of 2,4-dichloro-5-fluoropyridine and three equivalents of3-benzophenone in MeOH in a pressure tube at 110° C. for 24 h or in EtOHusing microwave at 175° C. for 10-20 min followed by aqueous work upgave N2,N4-bis(3-phenylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine asa white solid. LCMS: purity: 95.7%; MS (m/e): 489.29 (MH⁺).

7.3.1147N2,N4-Bis(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-2,4-pyrimidinediamine(R950378)

A solution ofN2,N4-bis(4-methoxycarbonylethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediaminein TfOH was heated for 2 hours at 100° C. Aqueous work up followed byflash chromatography on silica gel gaveN2,N4-bis(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ 9.36 (s, 1H), 9.14 (s, 1H), 8.06 (d,1H, J=2.4 Hz), 7.72-7.99 (m, 3H), 6.97 (d, J=7.2 Hz, 1H), 6.87 (d, J=7.2Hz, 1H), 4.42-4.52 (m, 4H), 2.70-2.78 (m, 4H); LCMS: purity: 94.3%; MS(m/e): 484.50 (MH⁺).

7.3.1148N2,N4-Bis(3-methylcarbonyloximephenyl)-5-fluoro-2,4-pyrimidinediamine(R950379)

A mixture ofN2,N4-bis(3-methylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine andhydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN2,N4-bis(3-methylcarbonyloximephenyl)-5-fluoro-2,4-pyrimidinediamine asa white solid. ¹H NMR (DMSO): δ 11.21 (s, 1H), 10.11 (s, 1H), 9.85 (s,1H), 6.54-8.23 (m, 9H), 4.32 (s, 2H), 2.63 (d, J=7.0 Hz, 3H), 2.47 (s,3H); LCMS: purity: 92.1%; MS (m/e): 393.06 (M−H⁻).

7.3.1149N2,N4-Bis(3-phenylcarbonyloximephenyl)-5-fluoro-2,4-pyrimidinediamine(R950380)

A mixture ofN2,N4-bis(3-phenylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine andhydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN2,N4-bis(3-phenylcarbonyloximephenyl)-5-fluoro-2,4-pyrimidinediamine asa white solid. LCMS: purity: 93.3%; MS (m/e): 486.05 (M−H⁻).

7.3.1150N2,N4-Bis(2,3-dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-2,4-pyrimidinediamine(R950381)

A mixture ofN2,N4-bis(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-2,4-pyrimidinediamineand hydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN2,N4-bis(2,3-dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-2,4-pyrimidinediamineas a white solid. LCMS: purity: 98.1%; MS (m/e): 449.03 (M−H⁻).

7.3.1151N4-(4-Acetyloxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950382)

A solution ofN4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein pyridine was treated with acetic anhydride at 22° C. for 16 hours.Aqueous work up gaveN4-(4-acetyloxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ 10.43 (bs, 1H), 9.62 (bs, 1H), 8.03(d, 1H, J=2.4 Hz), 7.10-7.83 (m, 7H), 6.83 (d, 1H, J=7.4 Hz), 6.52 (d,1H, J=7.2 Hz), 5.01 (m, 1H), 4.75 (s, 2H), 4.03-4.32 (m, 2H), 2.62 (s,3H), 2.23 (s, 3H), 1.93-2.13 (m, 2H); LCMS: purity: 92.1%; MS (m/e):393.06 (M−H⁻).

7.3.1152N4-(4-Azido-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950383)

A solution ofN4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein dry THF was treated with 2 equivalents of DPPA and DBU. The mixturewas stirred for 3 hours at 22° C., concentrated to dryness and purifiedby flash chromatography on silica gel to giveN4-(4-azido-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ 10.09 (bs, 1H), 9.83 (bs, 1H), 8.18(d, 1H, J=2.4 Hz), 7.97 (m, 1H), 7.11-7.61 (m, 6H), 6.82 (d, 1H, J=7.8Hz), 6.62 (d, 1H, J=7.2 Hz), 4.78 (s, 2H), 4.03-4.33 (m, 3H), 2.62 (s,3H), 1.93-2.13 (m, 2H); LCMS: purity: 97.9%; MS (m/e): 463.07 (MH⁺).

7.3.1153N4-(4-Benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950385)

A solution ofN4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein THF was treated with bortrifluoride etherate at 80° C. for 8 hours.Aqueous work up gaveN4-(4-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ 9.18 (s, 1H), 9.14 (s, 1H), 8.03 (d,J=2.4 Hz, 1H), 7.93 (bs, 1H), 5.86-7.48 (m, 9H) 4.73-4.74 (m, 2H), 4.33(s, 2H), 2.62 (s, 3H); LCMS: purity: 96.5%; MS (m/e): 420.07 (M−H⁻).

7.3.1154N4-(3-Hydroxymethylen-4-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950386)

A mixture of equimolar amounts of2-chloro-N4-(3-hydroxymethylen-4-methoxyphenyl)-5-fluoro-4-aminopyridineand 3-(N-methylamino)carbonylmethylene oxyaniline in MeOH in a pressuretube at 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20min followed by aqueous work up gaveN4-(3-hydroxymethylen-4-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 89.2%; MS (m/e): 410.5 (MH⁺).

7.3.1155N4-(3-Amino-4-ethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950388)

A mixture of2-chloro-N4-(3-amino-4-ethoxyphenyl)-5-fluoro-4-aminopyridine and 3equivalents of 3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in apressure tube at 110° C. for 24 h or in EtOH using microwave at 175° C.for 10-20 min followed by aqueous work up gaveN4-(3-amino-4-ethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 95.1%; MS (m/e): 427.18 (MH⁺).

7.3.1156N4-(4-Ethoxy-3-hydroxysulfonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950389)

A solution ofN4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein HOAc was treated with sodium nitrate followed by addition ofconcentrated aqueous HCl and copper dichloride. The mixture was stirredfor 2 hours at 22° C. for 8 hours and purified by aqueous work upfollowed by column chromatography on silica gel to giveN4-(4-ethoxy-3-hydroxysulfonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 82.3%; MS (m/e): 474.09 (M−H⁻).

7.3.1157N2,N4-Bis(3-methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950391)

A mixture of 2,4-dichloro-5-fluoropyridine and three equivalents of3-methoxycarbonyl-4-trifluoromethoxyaniline in MeOH in a pressure tubeat 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20 minfollowed by aqueous work upN2,N4-bis(3-methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamineas a white solid. ¹HNMR (DMSO): δ 9.96 (s, 1H), 9.82 (s, 1H), 8.16-8.26(m, 4H), 7.91 (dd, 1H, J=3.0, 7.2 Hz), 7.42 (d, 1H, J=7.2 Hz), 7.31 (d,1H, J=7.2 Hz), 3.77 (s, 3H), 3.75 (s, 3H); LCMS: purity: 93.0%; MS(m/e): 565.37 (MH⁺).

7.3.1158 N4-(3-Methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950392)

A mixture of equimolar amounts of2-chloro-N4-(3-methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-4-aminopyridineand 3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in a pressuretube at 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20min followed by aqueous work up gaveN4-(3-methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 95.8%; MS (m/e): 510.41 (MH⁺).

7.3.1159N4-(4-Acetylamino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950393)

A solution ofN4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein dry MeCN was treated with concentrated sulfuric acid. The mixture wasstirred for 3 hours at 22° C., concentrated to dryness and purified byflash chromatography on silica gel to giveN4-(4-acetylamino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ 10.46 (bs, 1H), 9.52 (bs, 1H), 7.98(d, 1H, J=2.4 Hz), 7.12-7.73 (m, 7H), 6.66 (d, 1H, J=7.2 Hz), 6.49 (d,1H, J=7.2 Hz), 4.75 (s, 2H), 4.03-4.32 (m, 2H), 3.80 (m, 1H), 2.64 (s,3H), 2.143 (s, 3H), 1.90-2.11 (m, 2H); LCMS: purity: 92.1%; MS (m/e):393.06 (M−H⁻). LCMS: purity: 96.2%; MS (m/e): 479.13 (M−H⁻).

7.3.1160N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine HCl salt (R950399)

A solution ofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein MeOH was treated with 1 equivalent of 1 N aqueous HCl. The clearsolution was concentrated to dryness and the remaining solid was washedwith dry acetone to give the HCl salt ofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 98.2%; MS (m/e): 438.98 (MH⁺).

7.3.1161N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine succinic acid salt (R950400)

A solution ofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein MeOH was treated with 1 equivalent of succinic acid. The clearsolution was concentrated to dryness and the remaining solid wascrystallized from dry acetone to give the succinic acid salt ofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 98.1%; MS (m/e): 438.98 (MH⁺).

7.3.1162N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine maleic acid salt (R950401)

A solution ofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein MeOH was treated with 1 equivalent of maleic acid. The clear solutionwas concentrated to dryness and the remaining solid was crystallizedfrom dry acetone to give the maleic acid salt ofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 97.9%; MS (m/e): 438.98 (MH⁺).

7.3.1163N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine fumaric acid salt (R950402)

A solution ofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein MeOH was treated with 1 equivalent of fumaric acid. The clearsolution was concentrated to dryness and the remaining solid wascrystallized from dry acetone to give the fumaric acid salt ofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 97.9%; MS (m/e): 438.98 (MH⁺).

7.3.1164N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine citric acid salt (R950403)

A solution ofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein MeOH was treated with 1 equivalent of citric acid. The clear solutionwas concentrated to dryness and the remaining solid was crystallizedfrom dry acetone to give the citric acid salt ofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 97.9%; MS (m/e): 438.98 (MH⁺).

7.3.1165N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine HNO₃ salt (R950404)

A solution ofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein MeOH was treated with 1 equivalent of 1 N aqueous HNO₃. The clearsolution was concentrated to dryness and the remaining solid was washedwith dry acetone to give the nitric acid salt ofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine as a white solid. LCMS:purity: 98.2%; MS (m/e): 438.98 (MH⁺).

7.4 Synthesis of Prodrugs

Exemplary prodrugs according to structural formula (II) were synthesizedas described below.

7.4.1N-2(4)-Acetyl-N2,N4-bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926233)

A mixture ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine,acetyl chloride (4 equivalents), pyridine (4 equivalents) in CH₂Cl₂ wasstirred at room temperature for 48 h. After an aqueous work up theresidue was chromatographed on silica gel to giveN-2(4)-acetyl-N2,N4-bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.23 (d, 1H, J=5.4 Hz), 7.03 (d, 1H, J=2.4 Hz),7.90-7.80 (m, 3H), 6.76 (m, 2H), 4.28 (bs, 4H), 2.10 (s, 3H); ¹⁹F NMR(CDCl₃): −42125; LCMS: ret. time: 27.94 min.; purity: 99%; MS (m/e): 439(MH⁺).

7.4.2N2,N4-Bis(3-N-acetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine(R950244)

N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,dimethylaminopyridine (DMAP) and acetic anhydride were refluxed inpyridine for 1 hour. The mixture was cooled to room temperature,concentrated, and the residue was subjected to column chromatography onsilica gel (CHCl₃:Acetone, 2:1) to giveN2,N4-bis(3-N-acetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine.LCMS: ret. time: 17.03 min.; purity: 87.0%; MS (m/e): 478.89 (MH⁺).

7.4.3N4-(3-N,N-Diacetylaminophenyl)-N2-(3-N-acetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine(R950245)

N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,dimethylaminopyridine (DMAP) and acetic anhydride were refluxed inpyridine for 1 hour. The mixture was cooled to room temperature,concentrated, and the residue was subjected to column chromatography onsilica gel (CHCl₃:Acetone, 2:1) to giveN4-(3-N,N-diacetylaminophenyl)-N2-(3-N-acetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine.LCMS: ret. time: 19.27 min.; purity: 92.6%; MS (m/e): 521.01 (MH⁺).

7.4.4N4-(3-N-Acetylaminophenyl)-N2-(3-N,N-diacetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine(R950246)

N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,dimethylaminopyridine (DMAP) and acetic anhydride were refluxed inpyridine for 1 hour. The mixture was cooled to room temperature,concentrated, and the residue was subjected to column chromatography onsilica gel (CHCl₃:Acetone, 2:1) to giveN4-[3-N-acetylaminophenyl]-N2-(3-N,N-diacetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine.LCMS: ret. time: 18.89 min.; purity: 83.0%; MS (m/e): 520.97 (MH⁺).

7.4.5N2,N4-Bis(3-N,N-diacetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine(R950247)

N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,dimethylaminopyridine (DMAP) and acetic anhydride were refluxed inpyridine for 1 hour. The mixture was cooled to room temperature,concentrated, and the residue was subjected to column chromatography onsilica gel (CHCl₃:Acetone, 2:1) to giveN2,N4-bis(3-N,N-diacetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine.LCMS: ret. time: 21.51 min.; purity: 91.8%; MS (m/e): 563.00 (MH⁺).

7.5 The 2,4-Pyrimidinediamine Compounds of the Invention Inhibit FcεRIReceptor-Mediated Degranulation

The ability of the 2,4-pyrimidinediamine compounds of the invention toinhibit IgE-induced degranulation was demonstrated in a variety ofcellular assays with cultured human mast cells (CHMC) and/or mouse bonemarrow derived cells (BMMC). Inhibition of degranulation was measured atboth low and high cell density by quantifying the release of the granulespecific factors tryptase, histamine and hexosaminidase. Inhibition ofrelease and/or synthesis of lipid mediators was assessed by measuringthe release of leukotriene LTC4 and inhibition of release and/orsynthesis of cytokines was monitored by quantifying TNF-α, IL-6 andIL-13. Tryptase and hexosaminidase were quantified using fluorogenicsubstrates as described in their respective examples. Histamine, TNFα,IL-6, IL-13 and LTC4 were quantified using the following commercialELISA kits: histamine (Immunotech #2015, Beckman Coulter), TNFα(Biosource #KHC3011), IL-6 (Biosource #KMC0061), IL-13 (Biosource#KHC0132) and LTC4 (Cayman Chemical #520211). The protocols of thevarious assays are provided below.

7.5.1 Culturing of Human Mast and Basophil Cells

Human mast and basophil cells were cultured from CD34-negativeprogenitor cells as described below (see also the methods described incopending U.S. application Ser. No. 10/053,355, filed Nov. 8, 2001, thedisclosure of which is incorporated herein by reference).

7.5.1.1 Preparation of STEMPRO-34 Complete Medium

To prepare STEMPRO-34 complete medium (“CM”), 250 mL STEMPRO-34™ serumfree medium (“SFM”; GibcoBRL, Catalog No. 10640) was added to a filterflask. To this was added 13 mL STEMPRO-34 Nutrient Supplement (“NS”;GibcoBRL, Catalog No. 10641) (prepared as described in more detail,below). The NS container was rinsed with approximately 10 mL SFM and therinse added to the filter flask. Following addition of 5 mL L-glutamine(200 mM; Mediatech, Catalog No. MT 25-005-CI and 5 mL 100×penicillin/streptomycin (“pen-strep”; HyClone, Catalog No. SV30010), thevolume was brought to 500 mL with SFM and the solution was filtered.

The most variable aspect of preparing the CM is the method by which theNS is thawed and mixed prior to addition to the SFM. The NS should bethawed in a 37° C. water bath and swirled, not vortexed or shaken, untilit is completely in solution. While swirling, take note whether thereare any lipids that are not yet in solution. If lipids are present andthe NS is not uniform in appearance, return it to the water bath andrepeat the swirling process until it is uniform in appearance. Sometimesthis component goes into solution immediately, sometimes after a coupleof swirling cycles, and sometimes not at all. If, after a couple ofhours, the NS is still not in solution, discard it and thaw a freshunit. NS that appears non-uniform after thaw should not be used.

7.5.1.2 Expansion of CD34+ Cells

A starting population of CD34-positive (CD34+) cells of relatively smallnumber (1-5×10⁶ cells) was expanded to a relatively large number ofCD34-negative progenitor cells (about 2-4×10⁹ cells) using the culturemedia and methods described below. The CD34+ cells (from a single donor)were obtained from Allcells (Berkeley, Calif.). Because there is adegree of variation in the quality and number of CD34+ cells thatAllcells typically provides, the newly delivered cells were transferredto a 15 mL conical tube and brought up to 10 mL in CM prior to use.

On day 0, a cell count was performed on the viable (phase-bright) cellsand the cells were spun at 1200 rpm to pellet. The cells wereresuspended to a density of 275,000 cells/mL with CM containing 200ng/mL recombinant human Stem Cell Factor (“SCF”; Peprotech, Catalog No.300-07) and 20 ng/mL human fit-3 ligand (Peprotech, Catalog No. 300-19)(“CM/SCF/flt-3 medium”). On about day 4 or 5, the density of the culturewas checked by performing a cell count and the culture was diluted to adensity of 275,000 cells/mL with fresh CMISCF/flt-3 medium. On about day7, the culture was transferred to a sterile tube and a cell count wasperformed. The cells were spun at 1200 rpm and resuspended to a densityof 275,000 cells/mL with fresh CM/SCF/flt-3 medium.

This cycle was repeated, starting from day 0, a total of 3-5 times overthe expansion period.

When the culture is large and being maintained in multiple flasks and isto be resuspended, the contents of all of the flasks are combined into asingle container prior to performing a cell count. This ensures that anaccurate cell count is achieved and provides for a degree of uniformityof treatment for the entire population. Each flask is checked separatelyfor contamination under the microscope prior to combining to preventcontamination of the entire population.

Between days 17-24, the culture can begin to go into decline (i.e.,approximately 5-10% of the total number of cells die) and fail to expandas rapidly as before. The cells are then monitored on a daily basisduring this time, as complete failure of the culture can take place inas little as 24 hours. Once the decline has begun, the cells arecounted, spun down at 850 rpm for 15 minutes, and resuspended at adensity of 350,000 cells/mL in CMISCF/flt-3 medium to induce one or twomore divisions out of the culture. The cells are monitored daily toavoid failure of the culture.

When greater than 15% cell death is evident in the progenitor cellculture and some debris is present in the culture, the CD34-negativeprogenitor cells are ready to be differentiated.

7.5.1.3 Differentiation of CD34-Negative Progenitor Cells into MucosalMast Cells

A second phase is performed to convert the expanded CD34-negativeprogenitor cells into differentiated mucosal mast cells. These mucosalcultured human mast cells (“CHMC”) are derived from CD34+ cells isolatedfrom umbilical cord blood and treated to form a proliferated populationof CD34-negative progenitor cells, as described above. To produce theCD43-negative progenitor cells, the resuspension cycle for the culturewas the same as that described above, except that the culture was seededat a density of 425,000 cells/mL and 15% additional media was added onabout day four or five without performing a cell count. Also, thecytokine composition of the medium was modified such that it containedSCF (200 ng/mL) and recombinant human IL-6 (200 ng/mL; Peprotech,Catalog No. 200-06 reconstituted to 100 ug/mL in sterile 10 mM aceticacid) (“CMISCF/IL-6 medium”).

Phases I and II together span approximately 5 weeks. Some death anddebris in the culture is evident during weeks 1-3 and there is a periodduring weeks 2-5 during which a small percentage of the culture is nolonger in suspension, but is instead attached to the surface of theculture vessel.

As during Phase I, when the culture is to be resuspended on day seven ofeach cycle, the contents of all flasks are combined into a singlecontainer prior to performing a cell count to ensure uniformity of theentire population. Each flask is checked separately for contaminationunder the microscope prior to combining to prevent contamination of theentire population.

When the flasks are combined, approximately 75% of the volume istransferred to the communal container, leaving behind about 10 mL or soin the flask. The flask containing the remaining volume was rappedsharply and laterally to dislodge the attached cells. The rapping wasrepeated at a right angle to the first rap to completely dislodge thecells.

The flask was leaned at a 45 degree angle for a couple of minutes beforethe remaining volume was transferred to the counting vessel. The cellswere spun at 950 rpm for 15 min prior to seeding at 35-50 mL per flask(at a density of 425,000 cells/mL).

7.5.1.4 Differentiation of CD34-Negative Progenitor Cells intoConnective Tissue-Type Mast Cells

A proliferated population of CD34-negative progenitor cells is preparedas above and treated to form a tryptase/chymase positive (connectivetissue) phenotype. The methods are performed as described above formucosal mast cells, but with the substitution of IL-4 for IL-6 in theculture medium. The cells obtained are typical of connective tissue mastcells.

7.5.1.5 Differentiation of CD34-Negative Progenitor Cells into BasophilCells

A proliferated population of CD34-negative progenitor cells is preparedas described in Section 6.4.1.2, above, and used to form a proliferatedpopulation of basophil cells. The CD34-negative cells are treated asdescribed for mucosal mast cells, but with the substitution of IL-3 (at20-50 ng/mL) for IL-6 in the culture medium.

7.5.2 CHMC Low Cell Density IgE Activation: Tryptase and LTC4 Assays

To duplicate 96-well U-bottom plates (Costar 3799) add 65 ul of compounddilutions or control samples that have been prepared in MT [137 mM NaCl,2.7 mM KCl, 1.8 mM CaCl₂, 1.0 mM MgCl₂, 5.6 mM Glucose, 20 mM Hepes (pH7.4), 0.1% Bovine Serum Albumin, (Sigma A4503)] containing 2% MeOH and1% DMSO. Pellet CHMC cells (980 rpm, 10 min) and resuspend in pre-warmedMT. Add 65 ul of cells to each 96-well plate. Depending on thedegranulation activity for each particular CHMC donor, load 1000-1500cells/well. Mix four times followed by a 1 hr incubation at 37° C.During the 1 hr incubation, prepare 6× anti-IgE solution [rabbitanti-human IgE (1 mg/ml, Bethyl Laboratories A80-109A) diluted 1:167 inMT buffer]. Stimulate cells by adding 25 ul of 6× anti-IgE solution tothe appropriate plates. Add 25 ul MT to un-stimulated control wells. Mixtwice following addition of the anti-IgE. Incubate at 37° C. for 30minutes. During the 30 minute incubation, dilute the 20 mM tryptasesubstrate stock solution [(Z-Ala-Lys-Arg-AMC2TFA; Enzyme SystemsProducts, #AMC-246)]1:2000 in tryptase assay buffer [0.1 M Hepes (pH7.5), 10% w/v Glycerol, 10 uM Heparin (Sigma H-4898) 0.01% NaN₃]. Spinplates at 1000 rpm for 10 min to pellet cells. Transfer 25 ul ofsupernatant to a 96-well black bottom plate and add 100 ul of freshlydiluted tryptase substrate solution to each well. Incubate plates atroom temperature for 30 min. Read the optical density of the plates at355 nm/460 nm on a spectrophotometric plate reader.

Leukotriene C4 (LTC4) is also quantified using an ELISA kit onappropriately diluted supernatant samples (determined empirically foreach donor cell population so that the sample measurement falls withinthe standard curve) following the supplier's instructions.

7.5.3 CHMC High Cell Density IgE Activation: Degranulation (Tryptase,Histamine), Leukotriene (LTC4), and Cytokine (TNFalpha, IL-13) Assays

Cultured human mast cells (CHMC) are sensitized for 5 days with IL-4 (20ng/ml), SCF (200 ng/ml), IL-6 (200 ng/ml), and Human IgE (CP 1035K fromCortx Biochem, 100-500 ng/ml depending on generation) in CM medium.After sensitizing, cells are counted, pelleted (1000 rpm, 5-10 minutes),and resuspended at 1-2×10⁶ cells/ml in MT buffer. Add 100 ul of cellsuspension to each well and 100 ul of compound dilutions. The finalvehicle concentration is 0.5% DMSO. Incubate at 37° C. (5% CO₂) for 1hour. After 1 hour of compound treatment, stimulate cells with 6×anti-IgE. Mix wells with the cells and allow plates to incubate at 37°C. (5% CO₂) for one hour. After 1 hour incubation, pellet cells (10minutes, 1000 RPM) and collect 200 ul per well of the supernatant, beingcareful not to disturb pellet. Place the supernatant plate on ice.During the 7-hour step (see next) perform tryptase assay on supernatantthat had been diluted 1:500. Resuspend cell pellet in 240 ul of CM mediacontaining 0.5% DMSO and corresponding concentration of compound.Incubate CHMC cells for 7 hours at 37° C. (5% CO₂). After incubation,pellet cells (1000 RPM, 10 minutes) and collect 225 ul per well andplace in −80° C. until ready to perform ELISAS. ELISAS are performed onappropriately diluted samples (determined empirically for each donorcell population so that the sample measurement falls within the standardcurve) following the supplier's instructions.

7.5.4 BMMC High Cell Density IgE Activation: Degranulation(Hexosiminidase, Histamine), Leukotriene (LTC4), and Cytokine (TNFalpha,IL-6) Assays 7.5.4.1 Preparation of WEHI-Conditioned Medium

WEHI-conditioned medium was obtained by growing murine myelomonocyticWEHI-3B cells (American Type Culture Collection, Rockville, Md.) inIscove's Modified Eagles Media (Mediatech, Hernandon, Va.) supplementedwith 10% heat-inactivated fetal bovine serum (FBS; JRH Biosciences,Kansas City, Mo.), 50 μM 2-mercaptoethanol (Sigma, St. Louis, Mo.) and100 IU/mL penicillin-steptomycin (Mediatech) in a humidified 37° C., 5%CO₂/95% air incubator. An initial cell suspension was seeded at 200,000cells/mL and then split 1:4 every 3-4 days over a period of two weeks.Cell-free supernatants were harvested, aliquoted and stored at −80° C.until needed.

7.5.4.2 Preparation of BMMC Medium

BMMC media consists of 20% WEHI-conditioned media, 10% heat-inactivatedFBS (JHR Biosciences), 25 mM HEPES, pH7.4 (Sigma), 2 mM L-glutamine(Mediatech), 0.1 mM non-essential amino acids (Mediatech), 1 mM sodiumpyruvate (Mediatech), 50 μM 2-mercaptoethanol (Sigma) and 100 IU/mLpenicillin-streptomycin (Mediatech) in RPMI 1640 media (Mediatech). Toprepare the BMMC Media, all components are added to a sterile IL filterunit and filtered through a 0.2 μm filter prior to use.

7.5.4.3 Protocol

Bone marrow derived mast cells (BMMC) are sensitized overnight withmurine SCF (20 ng/ml) and monoclonal anti-DNP (10 ng/ml, Clone SPE-7,Sigma # D-8406) in BMMC media at a cell density of 666×10³ cells/ml.After sensitizing, cells are counted, pelleted (1000 rpm, 5-10 minutes),and resuspended at 1-3×10⁶ cells/ml in MT buffer. Add 100 ul of cellsuspension to each well and 100 ul of compound dilutions. The finalvehicle concentration is 0.5% DMSO. Incubate at 37° C. (5% CO₂) for 1hour. After 1 hour of compound treatment, stimulate cells with 6×stimulus (60 ng/ml DNP-BSA). Mix wells with the cells and allow platesto incubate at 37° C. (5% CO₂) for one hour. After 1 hour incubation,pellet cells (10 minutes, 1000 RPM) and collect 200 ul per well of thesupernatant, being careful not to disturb pellet, and transfer to aclean tube or 96-well plate. Place the supernatant plate on ice. Duringthe 4-5 hour step (see next) perform the hexosiminidase assay. Resuspendcell pellet in 240 ul WEI-conditioned media containing 0.5% DMSO andcorresponding concentration of compound. Incubate BMMC cells for 4-5hours at 37° C. (5% CO₂). After incubation, pellet cells (1000 RPM, 10minutes) and collect 225 ul per well and place in −80° C. until ready toperform ELISAS. ELISAS are performed on appropriately diluted samples(determined empirically for each donor cell population so that thesample measurement falls within the standard curve) following thesupplier's instructions.

Hexosaminidase assay: In a solid black 96-well assay plate, add 50 uLhexosaminidase substrate(4-methylumbelliferyl-N-acetyl-3-D-glucosaminide; 2 mM) to each well.Add 50 uL of BMMC cell supernatant (see above) to the hexoseaminidasesubstrate, place at 37° C. for 30 minutes and read the plate at 5, 10,15, and 30 minutes on a spectrophotometer.

7.5.5 Basophil IgE or Dustmite Activation: Histamine Release Assay

The basophil activation assay was carried out using whole humanperipheral blood from donors allergic to dust mites with the majority ofthe red blood cells removed by dextran sedimentation. Human peripheralblood was mixed 1:1 with 3% dextran T500 and RBCs were allowed to settlefor 20-25 min. The upper fraction was diluted with 3 volumes of D-PBSand cells were spun down for 10 min at 1500 rpm, RT. Supernatant wasaspirated and cells were washed in an equal volume MT-buffer. Finally,cells were resuspended in MT-buffer containing 0.5% DMSO in the originalblood volume. 80 uL cells were mixed with 20 uL compound in the presenceof 0.5% DMSO, in triplicate, in a V-bottom 96-well tissue culture plate.A dose range of 8 compound concentrations was tested resulting in a10-point dose response curve including maximum (stimulated) and minimum(unstimulated) response. Cells were incubated with compound for 1 hourat 37° C., 5% CO₂ after which 20 uL of 6× stimulus [1 ug/mL anti-IgE(Bethyl Laboratories) 667 au/mL house dustmite (Antigen Laboratories)]was added. The cells were stimulated for 30 minutes at 37° C., 5% CO₂.The plate was spun for 10 min at 1500 rpm at room temperature and 80 uLthe supernatant was harvested for histamine content analysis using thehistamine ELISA kit supplied by Immunotech. The ELISA was performedaccording to supplier's instructions.

7.5.6 Results

The results of low density CHMC assays (Section 6.4.3), the high densityBMMC assays (Section 6.4.5) and the basophil assays (Section 6.4.6) areprovided in TABLE 1. The results of the high density CHMC assays(Section 6.4.4) are provided in TABLE 2. In TABLES 1 and 2, all reportedvalues are IC₅₀s (in μM). A value of “9999” indicates an IC₅₀>10 μM,with no measurable activity at a 10μM concentration. Most compoundstested had IC₅₀s of less than 10μM, with many exhibiting IC₅₀s in thesub-micromolar range.

7.6 The 2,4-Pyrimidinediamine Compounds Inhibit FcγRI Receptor-MediatedDegranulation

The ability of the 2,4-pyrimidinediamine compounds of the invention toinhibit FcγRI-mediated degranulation was demonstrated with CompoundsR921218, R921302, R921303, R940347, R920410, R927050, R940350, R935372,R920323, R926971 and R940352 in assays similar to those described inSection 6.4, with the exception that the cells were not primed with IgEand were activated with rabbit anti-human IgG Fab fragment (BethylLaboratories, Catalog No. A80-105).

All of the compounds tested exhibited IC₅₀s in the sub micromolar range.

TABLE 1 Low Density High Density CHMC CHMC CHMC Basophils BasophilsBasophils BMMC BMMC BMMC BMMC Test anti-IgE CHMC Ionomycin anti-IgE CHMCanti-IgE Ionomycin anti-IgE Ionomycin Dust mite anti-IgE Ionomycin BMMCanti-IgE anti-IgE BMMC anti-IgE anti-IgE Compound Tryptase Tryptase LTC4Hexos. Hexos. Histamine Histamine Histamine hexos Hexos. histamine LTC4TNF-alpha IL-6 R008951 R008952 R008953 R008955 R008956 R008958 R067934R067963 R070153 R070790 1.665 9999 R070791 R081166 R088814 R088815R091880 R092788 R908696 3.553 R908697 9999 9999 R909236 0.996 9999R909237 9999 9999 R909238 0.174 9999 <0.22 <0.22 0.521 0.432 <0.22R909239 0.264 9999 R909240 0.262 9999 R909241 0.181 9999 <0.22 <0.221.021 0.253 <0.22 R909242 0.567 9999 R909243 0.263 >10 R909245 0.2556.242 R909246 0.169 9999 R909247 2.393 9999 R909248 3.582 9999 R9092499999 9999 R909250 8.025 9999 R909251 0.138 9999 R909252 0.248 9999R909253 7.955 9999 R909254 0.136 9999 R920664 9999 9999 R920665 1.1 9999R920666 2.53 9999 R920668 3.2 9999 R920669 0.42 9999 R920670 2.18 9999R920671 9999 9999 R920672 9999 9999 R920818 9999 9999 R920819 10 9999R920820 9999 9999 R920846 9999 9999 R920860 1.009 9999 R920861 0.598 >10R920893 1.239 9999 R920894 0.888 5.566 R920910 0.751 7.922 R920917 1.5799.729 R921218 0.499 9999 0.55 0.6 9999 0.24 9999 0.302 0.133 9999 0.2030.766 0.274 0.100 R921219 0.059 9999 0.025 9999 0.020 0.069 0.058 0.0400.039 0.009 R925734 9.2 >10 9999 9999 R925747 1.021 3.1 3.1 R9257550.898 9999 R925757 2.8 9999 R925758 1.175 9999 R925760 4.85 9999 R9257656.8 9999 R925766 8.9 9999 R925767 10 R925768 9999 R925769 9999 R9257709999 R925771 0.5 2.8 0.22 R925772 9999 9999 R925773 0.673 9999 R9257740.435 9999 R925775 0.225 9999 0.2 R925776 2.1 9999 R925778 0.225 99990.18 R925779 0.265 9999 0.19 R925783 2.9 9999 R925784 3.2 9999 R9257852.5 9999 R925786 1.85 9999 R925787 9 9999 R925788 2.4 9999 R925790 99999999 R925791 9999 9999 R925792 6.25 9999 R925794 9999 9999 R925795 99999999 R925796 2 9999 R925797 0.85 9999 0.28 R925798 9999 9999 R9257999999 9999 R925800 9999 9999 R925801 9999 9999 R925802 9999 9999 R9258039999 9999 R925804 9999 9999 R925805 9999 9999 R925806 9999 9999 R9258079999 9999 R925808 9999 9999 R925810 9999 9999 R925811 3.3 9999 R9258125.8 9999 R925813 9999 9999 R925814 9999 9999 R925815 9999 9999 R925816 69999 R925819 9999 9999 R925820 9999 9999 R925821 9999 9999 R925822 99999999 R925823 9999 9999 R925824 9999 9999 R925837 9999 9999 R925838 99999999 R925839 9999 9999 R925840 9999 9999 R925841 9999 9999 R925842 7.39999 R925843 9999 9999 R925844 5.1 9999 R925845 2.3 9999 R925846 99999999 R925849 8.2 9999 R925851 0.925 9999 R925852 3 9999 R925853 99999999 R925854 9999 9999 R925855 4.2 9999 R925856 9.85 9999 R925857 5.959999 R925858 8.05 7.3 R925859 9999 9999 R925860 9999 9999 R925861 99999999 R925862 0.7 9999 R925863 0.274 9999 R925864 9999 9999 R925865 99999999 R926016 9999 9999 9999 9999 R926017 1.43 9999 0.53 9999 1.4 9.6R926018 9999 10 8.5 9999 R926037 9999 9999 9999 9999 R926038 9999 99999999 9999 R926039 9999 9999 9999 9999 R926058 9999 9999 9999 9999R926064 6.2 5.9 7.3 R926065 3.5 9999 9999 R926068 >10 7.4 8.2 R9260699.1 4.5 4.4 R926072 >10 9999 9999 R926086 2.5 9999 2.8 7.3 R926108 0.760.787 6.4 0.95 9999 0.9 9999 R926109 0.538 5.5 0.73 0.55 >10 0.15 99990.6 3.2 R926110 1.071 9999 1.42 1.2 >10 0.3 9999 1 4.5 R926113 0.4130.49 0.413 9999 0.27 9999 0.65 9999 R926114 3.427 8.1 1.7 10 9999 9999R926145 4.764 >10 2.4 8.8 R926146 1.59 0.761 6.7 1.35 5 R9261471.899 >10 2 7.1 R926206 >10 >10 6.6 8.6 R926209 >10 9999 10 9.1 R9262100.926 9999 0.8 700 9999 0.37 >10 0.6 >10 R926211 1.299 9.8 2.7 99991.55 >10 3.9 >10 R926212 0.654 9999 0.45 0.5 >10 0.5 5 R926213 1.639 5.51.75 >10 R926218 >10 9999 9999 R926219 1.102 6.7 2.5 3.2 R926220 >109999 9999 R926221 8.5 9.9 9999 R926222 >10 9999 9999 R926223 >10 99999999 R926224 >10 9999 9999 R926225 >10 9999 9999 R926228 >10 9999R926229 >10 R926230 >10 R926234 >10 9999 R926237 1.207 6.2 1.9 R9262400.381 1.7 0.145 R926241 7 9999 R926242 4.2 9999 R926243 3.1 9999 R9262453.1 9.4 R926248 0.9 9999 0.76 R926249 0.5 9999 0.25 R926252 2.8 R9262530.8 0.675 R926254 1.3 4 R926255 1.4 4.5 R926256 0.275 5.1 0.23 R9262571.5 7.5 R926258 0.9 9999 0.59 R926259 2.5 6.2 R926319 9999 9999 R9263209999 9999 R926321 9999 9999 R926325 9999 9999 R926331 9999 9999 R9263390.66 9999 R926340 3.23 9999 R926341 0.875 9999 R926342 10 9999 R9263769999 R926386 9999 9999 R926387 0.65 9999 0.7 R926394 9999 9999 R9263950.875 6.4 0.29 R926396 0.7 2.6 0.16 R926397 9999 9999 R926398 9999 9999R926399 9999 9999 R926400 9999 9999 R926401 9999 9999 R926402 9999 9999R926403 9999 9999 R926404 9999 9999 R926405 3.4 9999 R926406 9999 9999R926408 9.6 9999 R926409 3.15 9999 R926411 0.69 2.5 R926412 0.62 9999R926461 0.725 9999 R926467 1.175 8.8 R926469 9999 R926474 2.5 9999R926475 2.15 >10 R926476 0.6 7.7 R926477 0.27 9999 R926478 9999 R9264799999 R926480 1.9 9999 R926481 1.445 9999 R926482 1.037 >10 R926483 9999R926484 1.523 9999 R926485 4.012 9999 R926486 0.647 7.403 R926487 0.5548.867 1.25 R926488 0.331 >10 0.752 R926489 1.414 >10 R926490 1.571 9999R926491 1.158 >10 R926492 0.645 9999 R926493 0.25 9.181 0.078 R9264940.313 9999 0.078 R926495 0.121 >10 0.078 0.04 9999 0.038 0.056 0.0890.24 0.077 0.028 R926496 0.571 >10 R926497 0.138 9999 0.27 9999 0.205R926498 0.209 >10 <0.22 0.515 0.995 0.614 <0.22 R926499 0.29 >10 R9265000.418 >10 R926501 0.298 >10 0.609 9999 0.645 R926502 0.483 >10 0.4059999 0.491 R926503 0.452 >10 R926504 0.569 >10 R926505 0.145 9999 <0.22<0.22 <0.22 <0.22 <0.22 R926506 0.343 9999 R926508 0.127 9999 0.065 99990.054 0.086 0.107 0.162 0.054 0.026 R926509 1.16 9999 R926510 0.44 >10R926511 0.786 >10 R926514 9999 9999 R926516 1 9999 R926526 9999 9999R926527 9999 9999 R926528 8.75 9999 R926535 9999 9999 R926536 9999 9999R926555 9999 9999 R926559 7.7 9999 R926560 9999 9999 R926562 9999 9999R926563 9999 9999 R926564 3.75 9999 R926565 0.625 3.3 R926566 2.73 9999R926567 9.3 9999 R926569 0.61 3.07 R926571 9999 9999 R926572 1.8 6.08R926574 1.96 2.63 R926576 9999 9999 R926579 9999 9999 R926580 10 9999R926582 1.3 9999 R926583 9999 9999 R926584 9999 9999 R926585 9999 9999R926586 2.75 9999 R926587 9999 9999 R926588 7.85 9999 R926589 0.325 10R926591 2.62 9999 R926593 0.68 8.3 0.495 R926594 9999 9999 R926595 4.859999 R926604 2.85 9999 R926605 2.45 9999 R926614 0.228 9999 R9266150.445 9999 R926616 0.625 3.25 R926617 9.45 9999 R926620 8.35 9999R926623 9999 9999 R926662 9999 9999 R926663 9999 9999 R926675 0.63 9999R926676 0.76 9999 R926680 1.71 9999 R926681 0.775 9999 R926682 8.41 9999R926683 10 9999 R926688 2.25 >10 R926690 0.146 >10 R926696 0.309 >10R926698 9999 R926699 0.76 9999 R926700 0.157 >10 R926701 2.2 9999R926702 0.886 9999 R926703 0.525 9999 R926704 0.564 9999 R926705 0.2639999 0.533 R926706 0.07 2.406 0.078 R926707 0.214 9999 <0.056 <0.0560.39 0.088 <0.056 R926708 0.472 9999 R926709 0.858 9999 R926710 1.7639999 R926711 1.245 9999 R926712 1.084 9999 R926713 0.446 8.741 R9267140.428 >10 R926715 0.588 >10 R926716 1.06 9999 R926717 7.874 9999 R9267181.826 9999 R926719 0.1335 4.024 R926720 1.555 9999 R926721 4.441 9999R926722 5.96 9999 R926723 2.591 9999 R926724 2.059 9999 R926725 0.4319999 R926726 9999 9999 R926727 0.387 9999 R926728 0.482 >10 R9267300.251 9999 R926731 9999 9999 R926732 0.444 9999 R926733 1.496 9999R926734 4.493 9999 R926735 3.712 9999 R926736 0.288 9999 R926737 0.0599999 0.075 0.073 0.046 0.068 0.017 R926738 0.342 9999 R926739 0.508 9999R926740 4.422 9999 R926741 2.908 9999 0.961 1.025 9999 0.772 0.537R926742 0.127 0.043 9999 0.055 0.041 0.055 0.105 0.053 0.022 R9267439999 R926744 9999 R926745 0.083 9999 R926746 0.989 9999 R9267470.213 >10 R926748 0.345 >10 R926749 0.472 9999 R926750 0.361 >10 R9267510.598 9999 R926764 0.252 5.64 R926765 0.324 4.39 R926766 0.756 9999R926767 0.387 >10 R926768 0.443 >10 R926769 1.067 9999 R926770 0.5839999 R926771 2.049 9999 R926772 0.337 7.501 R926773 0.548 7.849 R9267741.934 7.935 R926775 3.47 >10 R926776 0.81 9999 R926777 0.378 9999R926778 0.414 9999 R926779 9999 9999 R926780 0.152 >10 <0.22 <0.22 0.461<0.22 <0.22 R926781 0.573 9999 R926782 0.173 >10 <0.22 <0.22 1.461 0.276<0.22 R926783 0.304 >10 R926784 0.252 9999 R926785 0.222 >10 0.989 0.5611.411 1.312 0.513 R926786 0.504 9999 R926787 5.422 9999 R926788 0.3366.341 R926789 2.315 9999 R926790 0.462 7.412 R926791 0.233 >10 0.064<0.056 0.896 0.205 <0.056 R926792 3.197 9999 R926793 3.073 9999 R9267952.041 >10 R926796 0.914 9999 R926797 2.235 9999 R926798 2.347 5.87R926799 9999 9999 R926800 4.581 9999 R926801 10 9999 R926802 1.251 >10R926803 1.541 >10 R926804 1.578 7.109 R926805 0.764 9999 R926806 0.3749999 R926807 0.291 9999 R926808 0.368 9999 R926809 0.78 3.052 R9268101.221 9999 R926811 3.662 9999 R926812 0.185 >10 R926813 0.152 9999R926814 1.101 9999 R926815 1.181 9999 R926816 0.084 9999 R935000 99999999 R935001 9999 9999 R935002 9999 9999 R935003 9999 9999 R935004 99999999 R935005 9999 9999 R935006 10 9.8 R935016 9999 9999 R935019 8.8 9999R935020 9999 9999 R935021 9999 9999 R935023 9999 9999 R935025 1.04 9999R935029 2.83 9999 R935075 0.93 9999 R935076 4.15 9999 R935077 9999 9999R935114 1.725 9999 R935117 9999 R935134 0.909 1.799 R935135 10 9999R935136 0.952 2.129 R935137 10 9999 R935138 0.096 0.552 <0.22 <0.220.373 0.409 <0.22 R935139 0.846 9999 R935140 0.275 0.959 R9351410.727 >10 R935142 0.873 >10 R935143 0.573 >10 R935144 0.63 9999 R9351450.548 >10 R935146 3.802 9999 R935147 1.404 9999 R935148 2.218 9.423R935149 0.708 >10 R935150 1.926 9.738 R935151 0.479 >10 R935152 0.5059.316 R935153 0.238 >10 R935154 0.127 >10 0.104 0.085 0.547 0.131 0.041R935155 0.401 9999 R935156 0.149 >10 <0.22 <0.22 0.433 0.22 <0.22R935157 0.256 4.656 R935158 0.551 >10 R935159 0.232 4.135 R9351600.202 >10 <0.22 0.317 0.876 0.484 <0.22 R935161 0.277 9999 R9351620.269 >10 R935163 9999 9999 R935164 0.204 9999 R935165 4.988 9999R935166 0.568 9999 R935167 2.132 >10 R935168 0.488 9.484 R935169 0.9998.007 R935170 0.673 9999 R935171 0.536 9999 R935172 1.385 6.808 R9351730.454 >10 R935174 1.384 9999 R935175 0.885 9999 R935176 1.169 9999R935177 0.889 >10 R935178 0.515 9999 R935179 0.557 9999 R935180 1.229999 R935181 1.76 9999 R935182 0.124 2.469 R935183 0.729 9999 R9351840.605 9999 R935185 0.351 6.642 R935186 0.211 9999 R935187 9.059 >10R935188 0.239 9999 R935189 0.619 9999 R935190 0.156 9999 R935191 0.1519999 0.068 0.043 0.213 0.071 0.027 R935192 0.337 9999 R935193 0.136 99990.08 0.048 0.312 0.092 0.037 R935194 0.11 9999 0.125 0.054 0.493 0.1180.034 R935196 0.117 9999 R935197 0.174 >10 R935198 0.126 >10 R9351990.45 >10 R935202 0.181 9.765 R935203 0.562 >10 R935204 0.554 9999R935205 2.959 9999 R935206 4.711 9999 R935207 9999 9999 R935208 1.2749999 R935209 0.526 1.035 R935211 1.238 9999 R935212 1.427 9999 R9352130.619 10 R935214 0.453 5.499 R935218 4.712 9999 R935219 5.409 9999R935220 3.789 9999 R940089 9999 9999 R940090 9999 9999 R940095 9999 9999R940100 9999 9999 R940215 0.845 9999 R940216 0.2675 7.3 R940217 99999999 R940222 9999 9999 R940233 0.132 >10 R940235 0.8 >10 R940250 R940251R940253 1.006 >10 R940254 0.986 9999 R940255 1.033 9999 R940256 1.1049999 R940257 0.667 9999 R940258 0.473 5.72 R940260 1.126 9999 R9402619999 9999 R940262 9999 9999 R940263 9999 9999 R940264 10 9999 R9402650.239 >10 0.981 0.306 1.211 1.131 0.486 R940266 9999 9999 R940267 3.1519999 R940269 1.654 9999 R940270 2.144 8.739 R940271 0.401 6.821 R9402750.862 9999 R940276 0.211 9999 0.136 0.073 0.332 0.251 <0.056 R9402770.141 9999 0.279 0.315 0.625 0.262 0.181 R940280 6.999 9999 R9402810.525 5.529 R940282 0.401 3.015 R940283 0.553 4.982 R940284 0.465 3.744R940285 3.499 9999 R940286 0.337 7.082 R940287 0.288 7.684 R940288 0.2089999 R940289 0.272 9999 R940290 0.116 9999 0.255 0.545 0.59 0.246 0.1R940291 0.396 9999 R940292 0.683 9999 R940293 9999 9999 R940294 1.3669999 R940295 0.126 8.812 R940296 0.41 >10 R940297 3.465 10 R945025 99999999 R945032 0.37 9999 R945033 9999 9999 R945034 1.85 9999 R945035 99999999 R945036 9999 9999 R945037 9999 9999 R945038 9999 9999 R945040 99999999 R945041 9999 9999 R945042 9999 9999 R945043 9999 9999 R945045 99999999 R945046 0.82 >10 R945047 0.845 9999 R945048 0.76 9999 R9450510.95 >10 R945052 0.425 2.48 R945053 0.1185 1.48 R945056 10 9999 R94505710 9999 R945060 0.9375 >10 R945061 10 9999 R945062 0.625 >10 R9450631.55 >10 R945064 0.53 >10 R945065 1.425 >10 R945066 5.2 nd R945067 9999nd R945068 9999 nd R945070 0.45 >10 R945071 0.205 >10 R945096 1.75 >10R945097 10 9999 R945109 1.025 >10 R945110 0.602 9999 R945117 4.077 9999R945118 0.668 9999 R945124 0.69 7.852 R945125 0.896 >10 R945126 99999999 R945127 0.704 8.955 R945128 0.685 8.8 R945129 1.003 >10 R9451301.874 9999 R945131 0.77 9999 R945132 0.571 8.77 R945133 1.064 >10R945134 9999 9999 R945135 0.986 8.245 R945137 1.649 >10 R945138 1.0586.733 R945139 1.016 >10 R945140 0.573 >10 R945142 1.049 >10 R9451440.244 9999 R945145 9999 >10 R945146 3.756 9999 R945147 3.546 9999R945148 0.307 9999 R945149 0.391 >10 R945150 0.467 >10 >2 >2 9999 0.7090.634 R945151 4.07 9999 R945152 6.94 9999 R945153 0.688 6.561 R9451551.878 >10 R945156 0.787 9999 R945157 1.477 9999 R945162 9999 9999R945163 0.922 4.251 R945164 10 9999 R945165 9999 9999 R945166 9999 9999R945167 0.761 9999 R945168 10 9999 R945169 10 9999 R945170 0.661 >10R945171 1.327 9999 R945172 1.179 9999 R945173 1.419 9999 R945175 1.6489999 R950082 9999 9999 R950083 9999 9999 R950090 9999 9999 R921302 0.379999 0.19 9999 0.282 R950092 9999 9999 R950093 0.64 5.55 R9501000.71 >10 R950107 0.46 >10 R950108 2.075 >10 R950109 7.95 R950120 3 9999R950121 4.25 >10 R950122 3.025 9999 R950123 3.25 8.45 R950125 1.375 6.3R950129 0.665 >10 R950130 4.9 R950131 9999 R950132 9 R950133 2.2 >10R950134 1.875 9999 R950135 0.85 >10 R950137 2.23 9999 R950138 9.5R950139 1.375 9999 R950140 2.825 9999 R950141 0.31 >10 R950142 10R950143 8.23 R950144 10 R950145 9999 R950146 9999 R950147 9999 R9501482.275 9999 R950149 10 9999 R950150 9999 9999 R950151 9999 R950152 10R950153 9999 R950154 2.075 9999 R950155 9999 R950156 9999 R950157 9999R950158 9.98 R950159 0.61 9999 R950160 1 9999 R950162 0.434 >10 R9501630.874 9999 R950164 1.893 9999 R950165 1.288 9999 R950166 1.889 9999R950167 9999 9999 R950168 6.496 8.653 R950169 1.273 9.518 R950170 99999999 R950171 0.585 >10 R950172 0.983 9999 R950173 2.368 >10 R9501744.618 9999 R950175 1.688 9999 R950176 1.342 9999 R950177 2.361 8.434R950178 0.688 >10 R950179 0.955 >10 R950180 0.278 9999 R950181 0.2549999 R950182 0.627 9999 R950183 4.797 9999 R950184 2.222 9999 R9501851.03 8.81 R950186 0.558 >10 R950187 0.724 >10 R950188 2.327 9999 R95018910 9999 R950190 1.573 9999 R950191 0.178 9999 <0.22 >2 0.401 <0.22 <0.22R950192 0.244 9999 R950193 0.61 9999 R950194 2.04 9999 R950195 0.4739999 R950196 2.2 9999 R950197 0.531 9999 R950198 0.406 >10 R950199 0.4089999 R950200 0.245 9999 R950201 0.261 9999 R950202 3.218 9999 R9502039.035 9999 R950204 6.285 9999 R950205 8.997 9999 R950206 3.66 >10R950207 0.164 9999 <0.22 <0.22 0.288 <0.22 <0.22 R950208 0.267 9999R950209 0.748 9999 R950210 10 9999 R950211 10 9999 R950212 0.253 9999R950213 9999 9999 R950214 10 9999 R950215 0.409 9999 R950216 0.327 9999R950217 0.34 9999 R950218 0.292 9999 R950219 0.439 9999 R950220 0.4899999 R950221 0.636 9999 R950222 0.865 9999 R950223 0.763 9999 R9502240.687 9999 R950225 5.283 9999 R950226 1.374 9999 R950227 1.029 9999R950229 0.98 9999 R950230 7.91 9999 R950231 1.968 9999 R950232 10 9999R950233 0.98 9999 R950234 10 9999 R950235 4.095 9999 R950236 0.955 9999R950237 9999 9999 R950238 10 9999 R950239 2.063 9999 R950240 1.766 9999R950241 3.275 9999 R950251 9999 9999 R950253 0.697 9999 R950254 0.4969999 R950255 10 9999 R908698 1.67 9999 R908699 0.217 9999 R908700 1.2739999 R908701 0.099 7.643 R908702 0.104 7.395 R908703 0.63 9999 R9087040.511 9999 R908705 0.801 9999 R908706 0.445 9999 R908707 1.834 9999R908709 2.414 R908710 1.838 99 R908711 1.761 R908712 0.075 99 R9087341.379 R909255 0.244 9999 R909259 0.43 9999 R909260 1.041 9999 R9092610.93 9999 R909263 0.289 9999 R909264 R909265 99 R909266 99 R909267 0.5899999 R909268 0.071 9999 R909290 0.226 R909292 1.172 R909308 0.671 9999R909309 0.083 9999 R920394 R920395 0.092 9999 R920396 R920397 R920398R920399 R920404 R920405 R920406 R920407 R920408 R920410 0.125 9999R920411 0.564 9999 R925745 1.766 9999 R926238 9999 R926752 0.338 9999R926753 0.108 9999 R926754 0.388 9999 R926755 1.693 9999 R926756 1.3659999 R926757 0.158 9999 R926759 0.688 9999 R926760 2.893 9999 R9267610.245 9999 R926762 0.386 9999 R926763 0.195 9999 R926794 1.382 9999R926826 0.613 9999 R926827 1.098 9999 R926828 0.306 9999 R926829 0.6889999 R926830 0.569 10 R926831 0.133 10 R926832 0.365 9999 R926833 1.1299999 R926834 0.145 9999 R926835 0.296 9999 R926836 10 9999 R926837 2.9949999 R926838 0.583 9999 R926839 0.161 9999 R926840 1.1 9999 R9268410.551 9999 R926842 7.733 9999 R926843 7.371 9999 R926844 1.1 9999R926845 2.558 7.812 R926846 0.86 6.264 R926847 1.479 6.264 R926848 0.25410 R926851 0.446 R926855 9999 9999 R926856 0.734 9999 R926857 1.209 9999R926859 R926860 1.949 99 R926862 0.774 9999 R926863 R926866 R9268703.294 R926871 2.146 R926874 0.638 9999 R926879 0.397 9999 R926880R926881 R926883 R926885 R926886 R926887 1.747 R926890 0.361 9999 R9268910.152 9999 R926892 0.685 9999 R926893 10 9999 R926894 9999 9999 R9268950.339 9999 R926896 1.622 9999 R926897 1.727 9999 R926898 1.1 9999R926899 1.1 9999 R926900 9999 9999 R926902 1.37 4.586 R926903 0.243 9999R926904 0.538 R926905 99 R926906 0.794 R926907 0.764 R926908 0.585R926909 0.379 R926913 0.548 9999 R926914 1.86 9999 R926915 1.713 9999R926916 1.958 9999 R926917 1.169 9999 R926918 2.521 9999 R926919 1.4139999 R926922 0.305 9999 R926923 0.346 9999 R926925 0.307 99 R9269260.401 9999 R926927 0.348 9999 R926928 0.575 9999 R926929 1.916 9999R926930 99 9999 R926931 R926932 0.31 9999 R926933 R926934 R926935 4.44R926936 R926937 R926938 R926939 3.615 R926940 7.754 R926941 4.195R926942 4.81 R926943 R926944 0.225 99 R926945 0.457 9999 R926946 R9269470.354 9999 R926948 0.246 9999 R926949 0.089 9999 R926950 99 9999 R9269510.183 9999 R926953 0.049 9999 R926954 0.284 9999 R926955 0.36 9999R926956 0.211 9999 R927016 1.408 R927017 2.449 R927018 1.446 R9270191.179 R927020 1.316 9999 R927023 0.918 9999 R935221 9999 9999 R9352220.52 9999 R935223 0.469 9999 R935224 4.578 9999 R935225 6.495 9999R935237 0.24 9999 R935238 1.854 9999 R935239 0.609 9999 R935240 0.6069999 R935242 2.855 9999 R935248 1.1 9999 R935249 1.1 9999 R935250 1.19999 R935251 R935252 R935253 R935255 0.374 9999 R935256 0.324 9999R935258 1.191 9999 R935259 1.777 9999 R935261 0.391 9999 R935262 0.5169999 R935263 0.106 10 R935264 0.135 9999 R935266 2.97 R935267 2.463R935268 1.059 R935269 1.715 R935271 R935276 2.33 R935277 22.883 8.9R935278 4.753 9999 R935279 0.889 9999 R935280 99 R935281 1.399 9999R935286 1.158 9999 R935287 0.403 9999 R935288 1.58 9999 R935289 1.6889999 R935290 0.34 9999 R935291 1.364 9999 R935292 0.483 9999 R9352930.141 9999 R935294 0.388 9999 R935295 1.943 9999 R935296 99 9999 R9352977.328 9999 R935298 0.252 99 R935299 0.21 9999 R935300 0.243 9999 R9353014.05 99 R935302 0.189 9999 R935303 0.244 99 R935304 0.188 9999 R9353050.495 9999 R935306 0.345 99 R935307 0.139 99 R935308 0.275 9999 R935309R935310 R935320 2.769 R935321 2.986 R935322 3.416 R935323 9999 R9353249999 R935336 0.341 9999 R935337 9999 R935338 0.411 9999 R935339 9999R935340 3.606 R935351 9999 9999 R935352 R935353 9999 9999 R935354 999999 R935355 9999 9999 R935356 99 R935357 99 9999 R935358 9999 9999R935359 1.027 9999 R935360 0.903 9999 R935361 1.438 9999 R935362 0.4099999 R935363 0.405 9999 R935364 0.563 9999 R935365 0.373 9999 R9353660.216 9999 R935367 0.053 9999 R940079 9999 R940110 9999 9999 R9402992.497 9999 R940300 10 9999 R940301 1.975 9999 R940304 9999 9999 R9403061.1 9999 R940307 0.291 9999 R940308 0.612 4.168 R940309 1.132 9999R940311 1.95 R940312 2.557 R940314 4.197 R940316 1.858 R940317 0.9139999 R940318 3.792 R940319 9999 R940321 9999 R940323 0.048 9999 R9403371.098 R940338 0.073 9999 R921303 0.033 99 R940345 1.712 R940346 0.142 99R940347 0.063 99 R940348 2.189 R940349 0.044 7.4 R940350 0.092 4 R9403510.12 2.7 R940352 0.101 9999 R940353 0.091 9999 R940354 0.115 99 R9452360.562 9999 R945237 0.461 9999 R945242 0.247 9999 R945263 1.642 R9213040.085 9999 R945299 R950244 9999 R950245 9999 R950246 9999 R950247 9999R950261 0.611 9999 R950262 0.285 9999 R950263 0.284 3.299 R950264 0.1989999 R950265 0.312 9999 R950266 0.645 9999 R950267 0.18 9999 R9502909999 9999 R950291 9999 9999 R950293 3.689 8.155 R950294 2.005 8.005R950295 2.041 8.795 R950296 0.495 9999 R950344 99 R950345 1.962 99R950346 0.345 9999 R950347 0.548 R950348 0.066 R950349 0.078 9999R950356 R950368 0.038 9999 R950371 R950372 1.348 9999 R950373 R9503740.599 9999 R950376 2.539 R950377 99 R950378 R950379 0.545 9999 R950380 39999 R950381 0.11 99 R950382 R950383 0.114 9999 R950385 R950386 0.973R950388 2.518 R950389 0.612 9999 R950391 999 9999 R950392 0.956 9999R950393 0.404 9999 R945028 R935241 R940298 R940302 R940303 R940305R935260 9999 R909258 R940313 9999 R940315 9999 R935275 9999 R940320 9999R940322 9999 9999 R926910 9999 9999 R926911 9999 9999 R926912 9999 9999R926853 9999 9999 R926852 9999 9999 R926854 9999 9999 R926920 9999 9999R926921 99 9999 R926924 99 9999 R926858 R926861 9999 9999 R945298 99999999 R940328 9999 R926869 R926873 9999 R926875 9999 R926876 9999 R9268779999 R940336 9999 R926878 9999 R926882 9999 R926884 9999 R926889 9999R920400 9999 R920401 9999 R920402 9999 R920403 9999 R940342 99 R9204099999 R940344 9999 R926888 9999 R926758 R927024 0.326 99 R927025 0.326R927026 9999 9999 R927027 9999 9999 R927028 0.208 9999 R927029 R9270300.26 9999 R927031 0.215 99 R927032 0.899 R927035 0.583 9999 R927036R927037 0.233 9999 R927038 1.05 9999 R927039 1.23 9999 R927040 1.05 9999R927041 0.788 9999 R927042 R935270 R935368 0.082 9999 R935369 0.255 9999R935370 R935371 0.794 9999 R935372 0.06 9999 R935373 0.274 9999 R9353740.356 9999 R935375 10 9999 R935376 R935377 R935378 0.566 9999 R935379R935380 1.61 99

TABLE 2 High Density Toxicity Toxicity CHMC CHMC CHMC CHMC CHMC CHMCToxicity Toxicity BJAB BJAB high density high density high density highdensity high density high density Jurkat Jurkat Light Cell hexostryptase histamine LTC4 TNF-alpha IL-13 Light Scat. Cell Titer Glo Scat.Titer Glo R008951 R008952 R008953 R008955 R008956 R008958 R067934R067963 R070153 R070791 R081166 R088814 R088815 R091880 R092788 99999999 R909241 3.736 R921219 0.124 0.121 0.162 0.034 0.190 0.175 >10 >10R925775 9999 9999 R925778 9999 9999 R925779 >10 9999 R925797 >10 9999R926108 >10 >10 R926109 0.783 0.906 1.827 0.808 1.504 1.664 >10 9999R926110 >10 >10 R921218 0.464 0.647 0.463 0.695 1.752 2.0776 >10 >10R926113 1.448 1.649 1.848 0.468 5.678 3.569 >10 >10 R926146 9999 9999R926210 >10 9999 R926240 10 9999 R926248 >10 9999 R926249 >10 9999R926253 9999 9999 R926256 >10 9999 R926258 9999 9999 R926387 >10 9999R926395 >10 9999 R926396 >10 9999 R926411 8.5 >10 R926486 1.088 1.3131.928 0.834 0.455 R926488 0.521 0.623 0.792 0.201 2.443 1.012 R9264930.889 1.093 1.324 0.474 >2 >4.33 R926494 0.640 >2 9999 0.326 9999R926495 0.100 0.235 0.066 0.241 0.362 0.449 >10 >10 R926496 0.429 0.5330.809 0.414 0.622 R926497 1.106 1.234 1.333 1.876 9999 R926501 >2 >29999 9999 9999 >4.33 >4.33 R926502 >2 >2 >2 1.807 >2 1.513 R926505 4.199R926508 0.170 0.434 0.105 0.505 0.763 >10 >10 R926510 0.921 1.115 1.6670.417 0.686 2.77 R926511 1.183 1.474 1.73 1.307 >2 >4.33 >4.33R926614 >10 >10 >10 6.442 R926696 <1.1 <1.1 <1.1 <1.1 <1.1 1.773 >5.0R926699 <1.1 <1.1 1.44 <1.1 <1.1 1.294 R926700 <1.1 <1.1 <1.1 <1.1 <1.12.053 R926703 1.512 1.947 >2 0.724 >2 R926704 >2 9999 9999 9999 9999R926705 1.007 1.256 0.641 0.494 9999 R926706 >2 9999 9999 1.491 9999R926742 0.104 0.217 0.080 0.385 0.667 9 >10 R926745 >10 >10 R926780 >5.0R926782 >4.33 >4.33 R935075 0.647 1.212 0.443 <0.22 >2 >4.33 >4.33R935154 >4.33 R935156 4.054 R940216 <1.1 <1.1 1.176 <1.1 3.188 3.006R940233 0.577 0.642 0.586 0.118 2.247 1.781 >4.33 >4.33 R945032 0.3570.458 0.439 0.0929 1.082 0.291 R945033 8.151 8.868 >10 5.983 R945071<1.1 <1.1 <1.1 <1.1 <1.1 <1.1 R945128 1.279 1.749 0.547 0.729 >2 NDR945140 0.994 1.112 1.551 1.714 9999 R945142 >2 >2 9999 >2 9999R945150 >4.33 >4.33 R921302 0.682 0.795 1.588 0.514 1.173 1.672 R9501410.567 0.618 0.627 0.201 1.059 0.798 R950207 >4.33

7.7 The 2,4-Pyrimidinediamine Compounds of the Invention SelectivelyInhibit the Upstream IgE Receptor Cascade

To confirm that many of the 2,4-pyrimidinediamine compounds of theinvention exert their inhibitory activity by blocking or inhibiting theearly IgE receptor signal transduction cascade, several of the compoundswere tested in cellular assays for ionomycin-induced degranulation, asdescribed below.

7.7.1 CHMC Low Cell Density Ionomycin Activation: Tryptase Assay

Assays for ionomycin-induced mast cell degranulation were carried out asdescribed for the CHMC Low Density IgE Activation assays (Section 6.4.3,supra), with the exception that during the 1 hour incubation, 6×ionomycin solution [5 mM ionomycin (Sigma I-0634) in MeOH (stock)diluted 1:416.7 in MT buffer (2 μM final)] was prepared and cells werestimulated by adding 25 μl of the 6× ionomycin solution to theappropriate plates.

7.7.2 Basophil Ionomycin Activation: Histamine Release Assay

Assays for ionomycin-induced basophil cell degranulation were carriedout as described for the Basophil IgE or Dustmite Activation Assay(Section 6.4.6, supra), with the exception that following incubationwith compound, cells were stimulated with 20 μl of 2 μM ionomycin.

7.7.3 Results

The results of the ionomycin-induced degranulation assays, reported asIC₅₀ values (in μM) are provided in TABLE 1, supra. Of the activecompounds tested (i.e., those that inhibit IgE-induced degranulation),the vast majority do not inhibit ionomycin-induced degranulation,confirming that these active compounds selectively inhibit the early (orupstream) IgE receptor signal transduction cascade.

These results were confirmed for certain compounds by measuringanti-IgE-induced and ionomycin-induced calcium ion flux in CHMC cells.In these Ca²⁺ flux tests, 10 μM R921218 and 10 μM R902420 inhibitedanti-IgE-induced Ca²⁺ flux, but had no effect on ionomycin-induced Ca²⁺flux (See FIG. 4). 7.8 The Inhibitory Effect of the2,4-Pyrimidinediamine Compounds of the Invention is Immediate

To test the immediacy of their inhibitory effect, certain2,4-pyrimidinediamines of the invention were added simultaneously withanti-IgE antibody activator in the cellular assays described above. Allcompounds tested blocked IgE-induced degranulation of CHMC cells to thesame extent as observed when the compounds were pre-incubated with CHMCcells for 10 or 30 min. prior to receptor cross-linking.

7.9 Kinetics of Pharmacological Activity In vitro

Compounds R921218, R921302, R921219, R926240, R940277, R926742, R926495,R909243 and R926782 were tested in washout experiments. In theexperiments, CHMC cells were either activated immediately with anti-IgEantibody in the presence of 1.25 μM compound (time zero), or thecompound was washed out followed by activation with anti-IgE antibody at30, 60 or 120 min. The inhibitory activity of these compounds wasgreatly diminished 30 min. after compound removal, indicating thatconstant exposure of mast cells to these compounds is required formaximal inhibition of degranulation The other compounds tested yieldedsimilar results.

7.10 Toxicity: T- and B-Cells

The ability of the compounds of the invention to exert their inhibitoryactivity without being toxic to cells of the immune system wasdemonstrated in cellular assays with B- and T-cells. The protocols forthe assays are provided below.

7.10.1 Jurkat (T-Cell) Toxicity

Dilute Jurkat cells to 2×10⁵ cells/ml in complete RPMI (10%heat-inactivated fetal bovine serum) media and incubate at 37° C., 5%CO₂ for 18 hours. Add 65 ul cells at 7.7×10⁵ cells/ml to a 96-wellV-bottom plate (TC-treated, Costar) containing 65 ul 2× compound (finalvehicle concentration is 0.5% DMSO, 1.5% MeOH). Mix, incubate plates for18-24 hr at 37° C., 5% CO₂. Toxicity was assessed by flow cytometricanalysis of cellular light scatter

7.10.2 BJAB (B-Cell) Toxicity

The B-cell line BJAB was cultured in log phase in RPMI1640+10%heat-inactivated fetal bovine serum, 1× L-glutamine, 1× penicillin, 1×streptavidin and 1× beta-mercaptoethanol at 37° C., 5% CO₂. First, BJABswere harvested, spun and resuspended in culture medium to aconcentration of 7.7×10⁵ cells/mL. 65 uL cells were mixed with 65 uLcompound, in duplicate and in the presence of 0.1% DMSO in a V-bottomed96-well tissue culture plate. Cells were incubated with compound atvarious dilutions at 37° C., 5% CO₂. Toxicity was assessed by flowcytometric analysis of cellular light scatter.

7.10.3 Toxicity: Cell Titer Glo Assay

Seed 50 μl cells (1×10⁶/ml) into each well containing 50 μl compound.The final vehicle concentration is 0.5% DMSO, 1.5% MeOH. Shake platesfor 1 minute to mix cells and compound. Incubate plates at 37° C. (5%CO₂) for 18 hours. Next day, harvest 50 μl cells from each well, add to50 μl Cell Titer Glo reagent (Invitrogen). Shake plates for 1 minute.Read on luminometer.

7.10.4 Results

The results of the T- and B-cell toxicity assays, reported as IC₅₀values (in μM), are presented in TABLE 2, supra. With a few exceptions(see TABLE 1), all compounds tested were non-toxic to both B- andT-cells at effective inhibitory concentrations. Assays performed withprimary B-cells yielded similar results.

7.11 The 2,4-Pyrimidine Compounds Are Tolerated In Animals

The ability of the compounds of the invention to exert their inhibitoryactivity at doses below those exhibiting toxicity in animals wasdemonstrated with compounds R921218, R921219 and R921302.

7.11.1 R921218

R921218 was studied in an extensive program of non-clinical safetystudies that concluded this agent to be well tolerated in both rodentsand non-rodents. To summarize the outcome of toxicology/non-clinicalsafety testing with R921218; this agent produced no dose limitingtoxicity by the intranasal route of administration in non-rodents(rabbits and primates) or by the oral route of administration in rodents(mice and rats) during 14-day repeat-dose toxicity studies at doses manyfold above the anticipated dose expected to produce efficacy in man.There were no adverse findings in a core safety pharmacology battery ofcardiovascular, respiratory and/or central nervous system function.There was no evidence for mutagenic or clastogenic potential in genetictoxicology testing nor were there untoward effects after exposure toskin and eyes. A short discussion of key toxicology studies is provided.

A 14-day repeat-dose intranasal toxicity study in Cynomolgus monkeys wasperformed at doses of 2.1, 4.5 or 6.3 mg/kg/day. In life parametersincluded: clinical observations, body weights, food consumption,ophthalmology, blood pressure, electrocardiography, hematology, clinicalchemistry, urinalysis, immunotoxicological assessment, gross necropsy,organ weights, toxicokinetic assessments and histopathology (includingthe nasal cavity). There were no adverse findings attributed to R921218in any study parameter and the NOAEL (no observed adverse effect level)was considered 6.3 mg/kg/day.

A 14-day repeat-dose intranasal toxicity study in New Zealand Whiterabbits was performed at doses of 1.7, 3.4 or 5.0 mg/kg/day. In lifeparameters included: clinical observations, body weights, foodconsumption, ophthalmology, hematology, clinical chemistry, grossnecropsy, organ weights, toxicokinetic assessments and histopathology(including the nasal cavity). There were no adverse findings attributedto R921218 in any study parameter and the NOAEL (no observed adverseeffect level) was considered 5.0 mg/kg/day.

7.11.2 R921219

In pilot dose finding studies a single dose oral dose of 600 mg/kg wasconsidered a NOEL (no observed effect level) while multiple (7-day)doses of 200 mg/kg/day and above were not tolerated.

In the in vitro Salmonella-Escherichia coli/Mammalian-Microsome ReverseMutation Assay (Ames test), R921219 was found to test positive in testerstrain TA1537, with and without metabolic activation, confirming theresults of an earlier study. R921219 was not found to adversely affectany of the other 4 tester strains. R921219 was not found to possessclastogenic potential when studied in an in vitro chromosomal aberrationassay.

7.11.3 R921302

Several non-GLP pilot toxicity studies have been conducted in rodents.In the mouse an oral dose of 1000 mg/kg was tolerated for up to 7-days.In a 14-day oral toxicity study in the mouse was conducted with doses of100, 300 and 1000 mg/kg. A dose of 1000 mg/kg was not tolerated, while adose of 300 mg/kg promoted evidence for histopathological changes in thevulva. A dose of 100 mg/kg was considered the NOAEL (no observed adverseeffect level) in the study. A 28-day oral toxicity study in the mousewas conducted at doses of 100 mg/kg q.d., 100 mg/kg b.i.d., 300 mg/kgq.d. and 300 mg/kg b.i.d. R921302 was not tolerated at 300 mg/kg q.d. orb.i.d. The lower doses (100 mg/kg q.d. or b.i.d.) appeared to be welltolerated (results of clinical and histopathology are not yet known). Inthe rat oral doses of 50, 150 and 300 mg/kg given for 32 days appearedto be well tolerated (results of clinical and histopathology are not yetknown).

In the in vitro Salmonella-Escherichia coli/Mammalian-Microsome ReverseMutation Assay (Ames test), R921302 was found to test positive in testerstrain TA98 with S9 and TA1537, with and without metabolic activation.R921302 was not found to adversely affect any of the other 3 testerstrains. R921302 was not clastogenic when assessed in an in vitrochromosomal aberration assay.

7.12 the 2,4-Pyrimidinediamine Compounds are Orally Bioavailable

Over 50 2,4-pyrimidinediamine compounds of the invention were tested fororal bioavailability. For the study, compounds were dissolved in variousvehicles (e.g. PEG 400 solution and CMC suspension) for intravenous andoral dosing in the rats. Following administration of the drug, plasmasamples were obtained and extracted. The plasma concentrations of thecompounds were determined by high performance liquidchromatography/tandem mass spectrometry (LC/MS/MS) methods.Pharmacokinetic analyses were performed based on the plasmaconcentration data. The pharmacokinetic parameters of interest includeClearance (CL), Volume of distribution at steady-state (Vss), terminalhalf-life (t_(1/4)), and oral bioavailability (% F).

These pharmacokinetic studies indicate that many of the2,4-pyrimidinediamine compounds are orally available, with % F up toapproximately 50% (in the range of 0-50%). The half-lives ranged from0.5 to 3 hr. In particular, Compounds R940350, R935372, R935193, R927050and R935391 exhibited good oral bioavailabilities and half-lives inrats. Thus, these studies confirm that these 2,4-pyrimidinediaminecompounds are suitable for oral administration.

7.13 the Compounds are Effective for the Treatment of Allergies

The in vivo efficacy of compounds R926109, R921218, R921219, R921302,R926495, R926508, R926742, R926745 and R945150 towards allergies wasevaluated in the mouse model of passive cutaneous anaphylaxis (PCA).This model provides a direct measure of IgE-induced degranulation oftissue mast cells. In this model, IgE primed animals are exposed to anallergen challenge, and the change in permeability of dermal vasculaturethat results from histamine release from mast cells is measured bychange in the amount of dye leakage into surrounding tissue. Inhibitionof mediator release by compounds that modulate mast cell degranulationis easily measured by extracting the dye from the tissue.

7.13.1 Study Protocol and Results

In the PCA assay mice are passively sensitized by intradermal injectionwith anti-dinitrophenol (DNP) IgE antibodies (Day 1). At predeterminedtimes animals are treated with the test agent (Day 0). The modulatoryeffect of the agent on cutaneous mast cell degranulation is measuredfollowing intravenous injection of DNP conjugated to human serum albumin(HSA-DNP), together with Evans blue dye. The resulting cross-linking ofthe IgE receptor and subsequent mast cell degranulation-induced increasein vascular permeability is determined by measuring the amount of dyeextravasation into the tissue. Dye is extracted from the tissue byformamide, and the absorbance of this extract is read at 620 nm. Theinhibitory effect of drug treatment is reported as the percentinhibition compared to vehicle treatment, that is, the percent reductionin A620.

Two compounds have been tested as positive controls: the histamineantagonist diphenhydramine and the serotonin antagonist cyproheptadine.Both mediators (histamine and serotonin) are released upon IgE-mediateddegranulation from the mouse mast cell. Both reference compounds inhibitthe PCA response; cyproheptadine was used routinely in subsequentexperiments. Cyproheptadine reproducibly inhibited the PCA response by61%+/−4% (8 mg/kg, i.p., 30 minutes pretreatment time, n=23experiments).

7.13.1.1 Results

A dose-dependent inhibition of the Fcεr-mediated vascular leakage wasobserved with increasing doses of R921218, R926109, R921219 andRR921302. These compounds were administered either in a solutionformulation (67% PEG/33% citrate buffer) or an aqueous suspension (1.5%Avicel). These results demonstrate the strong correlation betweencompound plasma levels, in vivo efficacy, and in vitro potency. The mostpotent compound, R921219, was active with circulating exposure levels ofapproximately 10 μg/ml (68% inhibition at a dose level of 100 mg/kg)compared with R921302, a relatively less potent molecule, which reducedplasma extravasation by 42% at a dose level of 100 mg/kg. Further, thelength of exposure to circulating compound was reflected in the durationof inhibitory activity. R921302, determined to be the most metabolicallystable compound in pharmacokinetics study, inhibited the vascularpermeability for 1-2 hours prior to antigen-induced receptor signaling,where after the efficacy began to decrease. These data are summarized inTABLE 3 and TABLE 4.

TABLE 3 Efficacy of R921218, R926109, R921219 and R921302 in the PCAAssay Plasma Pretreatment Dose % level Compound Route Vehicle time (min)(mg/kg) Inhibition (μg/ml) R921218 PO 67% PEG/33% 10 50 7 3 citratebuffer 100 11 4 200 50 18 R926109 PO 67% PEG/33% 15 50 22 N.D. citratebuffer 100 32 200 48 R921219 PO 1.5% 15 30 25 0.4 Avicel/water 100 68 4300 92 11 R921302 PO 1.5% 60 50 35 25 Avicel/water 100 42 38 150 56 64200 93 105

TABLE 4 Duration of action of R921219 and R921302 in the PCA AssayPlasma Pretreatment % level Compound Route Vehicle Dose (mg/kg) time(min) Inhibition (μg/ml) RR921302 PO 1.5% 200 30 89 88 Avicel/water 6083 53 120 82 61 240 37 8

Similar in vivo activity was observed with compounds R926495, R926508,R926742, R926745 and R926150, which were able to inhibit the PCAresponse after administration by the oral route in a PEG-basedformulation (data not shown).

7.14 the Compounds are Effective in the Treatment of Asthma

The efficacy of compounds R921218, R921302, R926495, R926508, R926742and R921219 in the treatment of asthma was demonstrated in the sheepmodel of allergic asthma. Sheep develop bronchoconstriction withinminutes of exposure to inhaled antigen (Ascaris suum), with maximalairflow obstruction during the early allergic response (EAR). Release ofpreformed mast cell mediators is likely responsible for this early phaseof airflow obstruction. In addition to the EAR, the sheep model allowsus to evaluate the effect of our compounds on the late asthmaticreaction (LAR) and non-specific airway hyperresponsiveness (AHR), whichoccur as a result of topical or local administration of allergen to theairway. In the sheep, AHR develops a few hours following antigenchallenge, and can persist for up to 2 weeks. The results describedbelow demonstrate the potential of the tested compounds to inhibit acascade of events that may be a result of release of cytokines from themast cell.

7.14.1 Study Protocol

In the sheep model of allergic asthma, sheep are administered aerosolsof test article via an endotracheal tube, followed by an aerosolchallenge with antigen extracted from the roundworm, Ascaris suum, towhich the sheep are naturally allergic. Allergen challenge leads todirect bronchoconstriction (both EAR and LAR) and a persistentnon-specific AHR. These three characteristics are similar to those seenin human allergic asthmatics. The activity of the test agent isdetermined by changes in the lung resistance (RL), which is calculatedfrom measurements of transpulmonary pressure, flow, and respiratoryvolume. The historical control data obtained from the same sheepfollowing saline treatment compared with an allergen challenge show thata sharp increase of RL occurs during the EAR and persists forapproximately 2-3 hours following allergen challenge. The LAR is a lesspronounced increase in RL, which starts approximately 5-6 hoursfollowing allergen challenge and is resolved by 8 hours post-challenge.Twenty-four hours after the challenge, a dose response to carbachol ismeasured to determine the AHR, which is expressed as the dose ofcarbachol required to increase RL by 400% over baseline. (Thismeasurement is referred to as the provocative concentration of carbacholthat elicits a 400% increase in RL over baseline (PC400). The data arecompared to historical control data for the same individual whenadministered a saline control aerosol and challenged with Ascaris suum.

7.14.2 Result

All the compounds tested showed inhibitory effects in the LAR and theAHR, and several of these agents inhibited the EAR as well. The optimalresponse for each compound in a series of studies to evaluate activityat several pretreatment times and using several different solution andsuspension formulations are shown in TABLE 5. The efficacy of R921218 onthe EAR appeared to be dependent on the formulation, with the greatesteffect seen at 30 mg/sheep administered as a solution aerosol in 10%ethanol. R926495, R926742, R926508 and R921219, administered in fourdifferent sheep at 45 mg/sheep in an aqueous suspension 60 minutes priorto allergen challenge, demonstrate that the LAR and AHR is blocked. Inaddition to these late parameters, the EAR was greatly reduced bytreatment with R921219, R926508 or R926495. The efficacy of RR921302 wasinvestigated using a 45% PEG400/55% citrate buffer vehicle. Under theseconditions, R921302, administered at 30 mg/sheep 60 minutes prior tochallenge, blocked the LAR and AHR, and EAR was unaffected.

These data clearly demonstrate that these compounds are able to blockthe asthmatic responses in allergic sheep. All compounds inhibited theAHR and LAR significantly when compared to the historical control. TheEAR was significantly inhibited by R921219, R926508 and R926495 (54%,21% and 33% respectively). In contrast, R921218, R921302 and R926742failed to inhibit the EAR when administered in an aqueous suspension.

TABLE 5 Efficacy Of Exemplary Compounds In A Sheep Model Of AllergicAsthma Dose Pretreatment EAR (% LAR (% AHR (% Compound (mg/sheep) time(min) Vehicle inhibition) inhibition) inhibition) R921218 30 15 10%ethanol 66 78 101 R926742 45 60 Aqueous suspension −19 87 94 R926495 4560 33 85 41 R926508 45 60 21 90 88 R921219 45 60 56 75 90 RR921302 30 6045% PEG400/55% −28 86 82 citrate buffer

7.15 the Compounds are Effective in the Treatment of Asthma

The efficacy of compounds R921304 and R921219 in the treatment of asthmawas also demonstrated in a mouse model of allergic asthma.

7.15.1 Study Protocol

Mice are sensitized to ovalbumin (chicken protein) in the presence of anadjuvant (Alum) by the intraperitoneal route on day 0 and day 7. Oneweek later, mice are challenged intranasally with ovalbumin on Days 14,15 and 16 (more stringent model) or on Day 14 (less stringent model).This sensitization and challenge regimen leads to airwayhyperresponsiveness and inflammation in the lungs, which are twodominant characteristics of human allergic asthma. In the mouse model,the in vivo airway responses are measured using a whole bodyplethysmograph which determines the PENH (enhanced Pause, BuxcoElectronics). The PENH is a dimensionless value comprised of the peakinspiratory flow (PIF), peak expiratory flow (PEF), time of inspiration,time of expiration and relaxation time, and is considered a validatedparameter of airway responsiveness. Responses to allergen challenge(OVA) are compared with animals challenged with saline only. Twenty-fourhours after challenge, mice are exposed to increasing doses ofmethacholine (muscarinic receptor agonist) which results in smoothmuscle contraction. The ovalbumin-challenged mice demonstrate asignificant airway hyperresponsiveness to methacholine when compared tothe saline challenged mice. In addition, a cellular infiltrate in theairway is observed in ovalbumin challenged mice when compared with thesaline challenged mice. This cellular infiltrate is mainly characterizedby eosinophils, but a smaller influx of neutrophils and mononuclearcells is also present.

The use of this model for the evaluation of small molecule inhibitors ofmast cell degranulation has been validated is several ways. First, usingmast cell deficient mice (W/W″) it has been shown that theovalbumin-induced responses are dependent upon the presence of mastcells. In the mast cell deficient mice, ovalbumin sensitization andchallenge did not result in airway hyperresponsiveness and eosinophilinflux. Second, the mast cell stabilizer, Cromolyn, was able to blockthe ovalbumin-induced airway hyperresponsiveness and inflammation (datanot shown). The use of this model to evaluate compounds for thetreatment of asthmatic responses that may be mediated by mechanismsother than mast cell stabilization, is further supported by theinhibitory effect of the steroids, dexamethasone and budesonide, onmethacoline-induced bronchocontriction.

7.15.2 Results

The efficacy of R921304 was evaluated by intranasal administration on 10consecutive days, from Day 7 through Day 16, at a dose level of 20mg/kg, with the last 3 doses administered 30 minutes prior to eithersaline or ovalbumin challenge. R921304 was able to inhibit theovalbumin-induced airway hyperresponsiveness to methacholine whencompared to the vehicle treated mice.

In a less stringent protocol, in which the mice were challenged withovalbumin only once on Day 14, R921219 administered subcutaneously at 70mg/kg in 67% PEG400/33% citrate buffer 30 minutes prior to saline orovalbumin challenge, demonstrates that R921219 completely blocked theovalbumin-induced airway hyperresponsiveness and cellular influx.

These results clearly demonstrate that R921219 and R921304 areefficacious in inhibiting the airway responses in a mouse model ofallergic asthma.

7.16 2,4-Pyrimidinediamine Compounds Inhibit Phosphorylation of ProteinsDownstream of Syk kinase in Activated Mast Cells

The inhibitory effect of the 2,4-pyrimidinediamine compounds on thephosphorylation of proteins downstream of Syk kinase was tested withcompounds R921218, R218219 and R921304 in IgE receptor-activated BMMCcells.

For the assay, BMMC cells were incubated in the presence of varyingconcentrations of test compound (0.08 μM, 0.4 μM, 2 μM and 10 μM) for 1hr at 37° C. The cells were then stimulated with anti-IgE antibody aspreviously described. After 10 min, the cells were lysed and thecellular proteins separated by electrophoresis (SDS PAGE).

Following electrophoresis, the phosphorylation of the proteins indicatedin FIGS. 7, 10 and 11A-D were assessed by immunoblot. Antibodies werepurchased from Cell Signaling Technology, Beverley, Mass.

Referring to FIGS. 7, 10 and 11A-D, the indicated compounds testedinhibited phosphorylation of proteins downstream of Syk, but notupstream of Syk, in the IgE receptor signaling cascade, confirming boththat the compounds inhibit upstream IgE induced degranulation, and thatthe compounds exhert their inhibitory activity by inhibiting Syk kinase.

7.17 2,4-Pyrimidinediamine Compounds Inhibit Syk Kinase in BiochemicalAssays

Several 2,4-pyrimidinediamine compounds were tested for the ability toinhibit Syk kinase catalyzed phosphorylation of a peptide substrate in abiochemical fluorescenced polarization assay with isolated Syk kinase.In this experiment, Compounds were diluted to 1%

DMSO in kinase buffer (20 mM HEPES, pH 7.4, 5 mM MgCl₂, 2 mM MnCl₂, 1 mMDTT, 0.1 mg/mL acetylated Bovine Gamma Globulin). Compound in 1% DMSO(0.2% DMSO final) was mixed with ATP/substrate solution at roomtemperature. Syk kinase (Upstate, Lake Placid N.Y.) was added to a finalreaction volume of 20 uL, and the reaction was incubated for 30 minutesat room temperature. Final enzyme reaction conditions were 20 mM HEPES,pH 7.4, 5 mM MgCl2, 2 mM MnCl₂, 1 mM DTT, 0.1 mg/mL acetylated BovineGamma Globulin, 0.125 ng Syk, 4 uM ATP, 2.5 uM peptide substrate(biotin-EQEDEPEGDYEEVLE-CONH2, SynPep Corporation). EDTA (10 mMfinal)/anti-phosphotyrosine antibody (1× final)/fluorescentphosphopeptide tracer (0.5× final) was added in FP Dilution Buffer tostop the reaction for a total volume of 40 uL according tomanufacturer's instructions (PanVera Corporation) The plate wasincubated for 30 minutes in the dark at room temperature. Plates wereread on a Polarion fluorescence polarization plate reader (Tecan). Datawere converted to amount of phosphopeptide present using a calibrationcurve generated by competition with the phosphopeptide competitorprovided in the Tyrosine Kinase Assay Kit, Green (PanVera Corporation).

The results of the assay are shown in TABLE 6, below:

TABLE 6 Compound No. IC50 (in μM) R926505 0.0703 R926508 0.1315 R9265940.7705 R926715 0.534 R926745 0.0925 R926782 0.1165 R926791 0.207 R9268130.4047 R926816 0.0615 R935138 0.2288 R935190 0.0465 R935191 0.045R935193 0.075 R935194 0.1687 R935196 0.2655 R940255 0.7705 R940256 2.787R940269 0.685 R940275 0.7335 R940276 0.1265 R940277 0.2143 R940290 0.187R945071 0.4295 R945140 0.611 R945142 2.007 R945144 0.383 R921302 0.2678R908702 0.0378 R908712 0.024 R909268 0.1253 R920410 0.157 R926753 0.108R926757 0.5103 R926834 0.292 R926839 0.055 R926891 0.1695 R926931 0.2553R935237 0.0455 R935293 0.0465 R935302 0.0265 R935304 0.042 R935307 0.057R935309 0.098 R935310 0.2003 R940323 0.062 R940338 0.028 R921303 0.00045R940347 0.0345 R921304 0.01275 R950368 0.0107 R950373 0.0665

These data demonstrate that all of the compounds tested, except forR945142 and R909236 inhibit Syk kinase phosphorylation with IC₅₀s in thesubmicromolar range. All compounds tested inhibit Syk kinasephosphorylation with IC₅₀s in the micromolar range. Although theforegoing invention has been described in some detail to facilitateunderstanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.Accordingly, the described embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope andequivalents of the appended claims. All literature and patent referencescited throughout the application are incorporated by reference into theapplication for all purposes.

We claim:
 1. A method, comprising administering to a subject a compoundaccording to Formula (I)

or a salt thereof, wherein: one of R² and R⁴ is a phenyl monosubstitutedwith (C1-C6) alkyl, —OR^(a), —O—C(O)OR^(a), —O—(CH₂)_(m)—C(O)OR^(a),—C(O)OR^(a), —O—(CH₂)_(m)—NR^(c)R^(c), —O—C(O)NR^(c)R^(c),—O—(CH₂)_(m)—C(O)NR^(c)R^(c), —O—C(NH)NR^(c)R^(c),—O—(CH₂)_(m)—C(NH)NR^(c)R^(c), —NH—(CH₂)_(m)—NR^(c)R^(c) or—[NHC(O)]R^(d); the other of R² and R⁴ is a phenyl monosubstituted ordisubstituted with R⁸; R² and R⁴ are different; R⁵ is fluoro, —CN, or(C1-C3) haloalkyl; each R⁸ is independently R^(a), R^(b), or R^(a)substituted with one R^(a) or R^(b); each R^(a) is (C1-C6) alkyl, or 3-8membered cycloheteroalkyl; each R^(b) is —OR^(a), —OCF₃, —NR^(c)R^(c),halogen, —CF₃, —CN, —NO₂, —N₃, —SO₂NR^(c)R^(c), —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(c)R^(c), or —C(NH)NR^(c)R^(c); each R^(c) is independentlyR^(a) or, alternatively, two R^(c) are taken together with the nitrogenatom to which they are bonded to form a 5 or 6-membered cycloheteroalkylor heteroaryl which may optionally include one or more of the same ordifferent additional heteroatoms and which may optionally be substitutedwith one or more of the same or different R^(a) or suitable R^(b)groups; each R^(d) is independently R^(a); and each m is independentlyan integer from 1 to
 2. 2. A method for treating a disease associatedwith tissue inflammation comprising administering to a subject aneffective amount of a compound having Formula (I)

or a salt thereof, wherein: one of R² and R⁴ is a phenyl monosubstitutedwith (C1-d10) alkyl, —OR^(a) optionally substituted with one R^(b)group, —O—C(O)OR^(a), —O—(CH₂)_(m)—C(O)OR^(a), —C(O)OR^(a),—O—(CH₂)_(m)—NR^(c)R^(c), —O—C(O)NR^(c)R^(c),—O—(CH₂)_(m)—C(O)NR^(c)R^(c), —O—C(NH)NR^(c)R^(c),—O—(CH₂)_(m)—C(NH)NR^(c)R^(c); —NH—(CH₂)_(m)—NR^(c)R^(c) or[NHC(O)]_(n)R^(d); the other of R² and R⁴ is a phenyl monosubstituted ordisubstituted with R⁸; R² and R⁴ are different; R⁵ is —NR^(c)R^(c),fluoro, —CN, or (C1-C6) alkyl optionally substituted with one or more ofthe same or different R⁸ groups; each R⁸ is independently R^(a) orR^(b); each R^(a) is H or (C1-C6) alkyl; each R^(b) is —OR^(a), —OCF₃,—NR^(c)R^(c), halogen, —CF₃, —CN, —NO₂, —N₃, —SO₂NR^(c)R^(c),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c),—C(NR^(a))NR^(c)R^(c), —C(NOH)R^(a), —C(NOH)NR^(c)R^(c); each R^(c) isindependently R^(a) or, alternatively, two R_(c) are taken together withthe nitrogen atom to which they are bonded to form a 5 to 8-memberedcycloheteroalkyl or heteroaryl which may optionally include one or moreof the same or different additional heteroatoms and which is optionallysubstituted with one or more of the same or different R^(a) or suitableR^(b) groups; each R^(d) is independently R^(a); each m is independentlyan integer from 1 to 2; and each n is independently an integer from 0 to3.